JP5319518B2 - Indoledione derivative - Google Patents

Abstract

A compound represented by the general formula (I-a): [wherein R 1a and R 2a each means hydrogen, lower cycloalkyl, lower alkyl, etc.; R 3a means hydrogen, lower cycloalkyl, lower alkyl, etc.; R 4a and R 5a each means lower alkyl, lower cycloalkyl, etc. or R 4a and R 5a are bonded to each other to form lower cycloalkylidene; and R 6a means lower alkyl, lower haloalkyl, etc.]. This compound functions as an LCE inhibitor and is useful as a therapeutic agent for various circulatory diseases, nervous diseases, metabolic diseases, reproductive diseases, digestive tract diseases, neoplasm, infectious diseases, etc.

Description

  The present invention is useful in the field of medicine. More specifically, the indole dione derivative of the present invention is a long chain fatty acid elongase (hereinafter sometimes abbreviated as LCE) inhibitor, and is used as an inhibitor for various cardiovascular diseases, nervous system diseases, metabolism. It is useful as a therapeutic agent for sex diseases, reproductive system diseases, gastrointestinal system diseases, neoplasms, infectious diseases and the like.

  Obesity is a condition in which neutral fat accumulates in adipocytes due to the persistence of excessive intake energy compared to energy consumption, resulting in a marked increase in body weight compared to standard weight (Itagaki). Eiji, “STEP Metabolism / Endocrine”, Kaiba Shobo, 1st Edition, 1998, p. 105; Non-Patent Document 1). It is known that excessive accumulated fat causes insulin resistance, diabetes, hypertension, hyperlipidemia, etc., and the risk of developing arteriosclerosis is greatly increased by combining these factors. Such symptoms are called metabolic syndrome. Furthermore, hypertriglyceridemia or obesity is, for example, pancreatitis, liver dysfunction, cancer such as breast cancer / uterine cancer / ovarian cancer / colon cancer / prostate cancer, menstrual abnormality, arthritis, gout, cholecystitis, gastroesophageal reflux, obesity It is known to increase the risk of hypoventilation syndrome (Pickwick syndrome), sleep apnea syndrome, and the like. In addition, it is well known that diabetes is likely to cause, for example, angina pectoris, heart failure, stroke, lameness, retinopathy, decreased visual acuity, renal failure, neuropathy, skin ulcer, infection, etc. [The Merck Manual of Medical Information (The Merck Manual of Medical Information), second home edition, Merck & Co, 2003; Non-Patent Document 2].

  LCE is an enzyme that exists in an endoplasmic reticulum in a cell, and is an enzyme that catalyzes a rate-limiting condensation step in an enzyme group that catalyzes a carbon chain elongation reaction of a fatty acid having 12 or more carbon chains. In mammals, many of the fatty acids newly synthesized in vivo have a chain length of 16-18 carbons. These long chain fatty acids are over 90% of the total fatty acids present in the cell. They are an important component of the membrane and a major component of adipose tissue, the largest energy storage organ in animals. It is the liver that has the highest rate of new fatty acid synthesis, and this synthesis converts excess glucose in the body into fatty acids. Glycolysis converts glucose to pyruvate, which is converted to citrate by mitochondria and transported to the cytosol. Cytosolic ATP citrate lyase produces acetyl CoA, a precursor of fatty acids and cholesterol. Acetyl CoA is carboxylated by acetyl CoA carboxylase (ACC) to form malonyl CoA. The multifunctional enzyme fatty acid synthase (FAS) uses malonyl CoA, acetyl CoA, and NADPH to elongate fatty acids by two carbons. The main end product of FAS in rodents is palmitoyl CoA with 16 carbon chains, which is extended by two carbons by LCE [Journal of Biological Chemistry (J. Biol Chem.), 276 (48), 45358-45366, (2001)] (Non-Patent Document 3). It is known that excessive enhancement of fatty acid synthesis in vivo causes an increase in neutral fat and the like, which in turn causes fat accumulation. For example, WO2005 / 005665 (Patent Document 1) shows a direct relationship between LCE and obesity. There is also a report that the expression level of mouse FACE (LCE) is changed by feeding (Matsuzaka T. et al., J. Lipid Res., 43 (6): 911-920 (2002); 4).

  LCE is also present in protozoa and nematodes, and is known to be involved in cell proliferation. For example, in trypanosomiasis, which is the cause of African trypanosomiasis (popular name: African sleeping sickness), long-chain fatty acids are synthesized by the fatty acid elongation pathway including LCE, and inhibition of intracellular fatty acid elongation reaction contributes to the growth of trypanosomes. (Lee SH et al., Cell, 126: 691-699 (2006); Non-Patent Document 5).

  Therefore, LCE inhibitors are expected to be useful as preventive and / or therapeutic agents for these diseases.

  The structures of some of the compounds according to the present invention are known per se, and the compounds are commercially available. However, there is no disclosure or suggestion that these compounds have an LCE inhibitory action.

International Publication No. 2005/005665 Pamphlet "STEP Metabolism / Endocrine", Kaiba Shobo, 1st Edition, 1998, p. 105 The Merck Manual of Medical Information, second home edition, Merck & Co, 2003. The Merck Manual of Medical Information (The Merck Manual of Medical Information), second home edition, Merck & Co, 2003 Journal of Biological Chemistry (J. Biol. Chem.), 276 (48), 45358-45366 (2001) J. et al. Lipid Res. 43 (6), 911-920 (2002). Cell, 126: 691-699 (2006)

  An object of the present invention is to provide a novel drug having an LCE inhibitory action.

  As a result of intensive studies, the present inventors have found that the compounds of the general formula (I)

[Where:
R ¹ and R ² are each independently substituted with a substituent selected from the group consisting of a hydrogen atom, a cyclo-lower alkyl group, an aryl group, a heteroaryl group, or a cyclo-lower alkyl group, an aryl group, and a heteroaryl group. Means an optionally substituted lower alkyl group;
R ⁴ and R ⁵ each independently represents a lower alkyl group, a cyclo lower alkyl group, an aryl group or an aralkyl group, or R ⁴ and R ⁵ together with an adjacent carbon atom together with a cyclo lower alkylidene May form a group;
R ⁶ represents a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group or a lower alkoxy lower alkyl group; the cyclo lower alkyl group, cyclo lower alkylidene group, aryl group, aralkyl group and heteroaryl group are each independently And may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ³ represents a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a lower alkyl group which may be substituted with a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group. The cyclo lower alkyl group, aryl group and heteroaryl group in R ³ are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group , Lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , _{^{-N (R 7) COR 8,}} -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R 8, _{^{SR 7, -SO 2 R 7,}} -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl And X represents —N (R ⁷ ) — or —O—], and the present invention was completed by finding that the compound represented by the above formula has an excellent LCE inhibitory action.

  The compound (I) according to the present invention has an LCE inhibitory action, and various diseases involving LCE such as hypertension, angina pectoris, heart failure, myocardial infarction, stroke, lameness, diabetic nephropathy, diabetic retinopathy Circulatory system diseases such as decreased vision, electrolyte abnormalities, arteriosclerosis, for example, bulimia, central nervous system diseases such as diabetic neuropathy, such as metabolic syndrome, obesity, diabetes, insulin resistance, hyperlipidemia, Metabolic disorders such as hypercholesterolemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fatty liver, abnormal hormone secretion, gout, fatty liver, reproductive system diseases such as menstrual disorders, sexual dysfunction, liver Gastrointestinal disorders such as dysfunction, pancreatitis, cholecystitis, gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory apnea syndrome such as sleep apnea syndrome, infectious diseases caused by bacteria, fungi, and parasites , Malignant neoplasms, arthritis, treatment agents such as inflammatory diseases such as skin ulcers, or are useful as herbicides.

  In particular, the compound (I) according to the present invention is useful as a therapeutic agent for, for example, diabetes, obesity or non-alcoholic fatty liver.

  The present invention relates to a compound represented by formula (I), a salt or ester thereof, and use thereof.

  The meanings of terms used in the present specification are described below, and the present invention is described in more detail.

  The “cyclo lower alkyl group” means a cycloalkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

  “Cyclo lower alkylidene group” means a cycloalkylidene group having 3 to 6 carbon atoms, such as 1,1-cyclopropylidene group, 1,1-cyclobutylidene group, 1,1-cyclopentylidene group, 1 , 1-cyclohexylidene group.

  Examples of the “aryl group” include a phenyl group and a naphthyl group.

  Examples of the “aryloxy group” include phenyloxy group, 1-naphthyloxy group, 2-naphthyloxy group and the like.

  The “heteroaryl group” is a 5-membered or 6-membered single atom containing 1 or 2 or more, preferably 1 to 3 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom. A cyclic heteroaryl group or a condensed cyclic heteroaryl group in which the monocyclic heteroaryl group and the aryl group are condensed, or the same or different monocyclic heteroaryl groups are condensed with each other, such as a pyrrolyl group, Furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl 1,3,4-thiadiazolyl group, pyridyl group, pyrazinyl group, pyrimi Nyl group, pyridazinyl group, 1,2,4-triazinyl group, 1,3,5-triazinyl group, indolyl group, benzofuranyl group, benzothienyl group, benzimidazolyl group, benzopyrazolyl group, benzoxazolyl group, benzoisoxa Zolyl group, benzothiazolyl group, benzoisothiazolyl group, indazolyl group, purinyl group, quinolyl group, isoquinolyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, pyrido [3,2-b ] A pyridyl group etc. are mentioned.

  “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group. Tert-butyl group, pentyl group, isopentyl group, hexyl group, isohexyl group and the like.

  The “aralkyl group” means the lower alkyl group substituted with one or two, preferably 1, aryl group at any substitutable position, for example, benzyl group, 1-phenylethyl group, phenethyl group. , 1-naphthylmethyl group, 2-naphthylmethyl group and the like.

  “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  “Halo lower alkyl group” means the lower alkyl group substituted with one or more, preferably 1 to 3, the same or different halogen atoms at any substitutable position, such as a fluoromethyl group, Examples thereof include a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1,2-difluoroethyl group, a chloromethyl group, a 2-chloroethyl group, a 1,2-dichloroethyl group, a bromomethyl group, and an iodomethyl group.

  The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, isobutoxy group. Group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, isohexyloxy group and the like.

  “Halo lower alkoxy group” means the lower alkoxy group substituted with one or more, preferably 1 to 3, the same or different halogen atoms at any substitutable position, such as a fluoromethoxy group, Difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 1,2-difluoroethoxy group, chloromethoxy group, 2-chloroethoxy group, 1,2-dichloroethoxy group, bromomethoxy group, iodomethoxy group, etc. Can be mentioned.

  The “lower alkoxy lower alkyl group” means the lower alkyl group substituted with the lower alkoxy at one or more, preferably 1 or 2, at any substitutable position. For example, a methoxymethyl group, ethoxymethyl Group, 2-methoxyethyl group, 1-methoxy-1-methylethyl group, 1,2-methoxyethyl group, 3-methoxypropyl group and the like.

  The term “salt” of a compound according to the present invention means a conventional pharmaceutically acceptable salt, for example, when it has a carboxyl group, it has a base addition salt, amino group or basic heterocyclic group in the carboxyl group. In this case, salts of acid addition salts in the basic heterocyclic group can be mentioned.

  Examples of the base addition salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt and ethanolamine. Examples thereof include organic amine salts such as salts, diethanolamine salts, triethanolamine salts, procaine salts, and N, N′-dibenzylethylenediamine salts.

  Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; for example, maleate, fumarate, tartrate, citrate, ascorbate, Organic acid salts such as trifluoroacetates; for example, sulfonates such as methanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, and the like.

  The “ester” of the compound according to the present invention means, for example, a pharmaceutically acceptable conventional compound having a carboxyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. Group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and other lower alkyl groups and other aralkyl groups such as benzyl group and phenethyl group Esters, esters with lower alkenyl groups such as allyl groups, 2-butenyl groups, esters with lower alkoxy lower alkyl groups such as methoxymethyl groups, 2-methoxyethyl groups, 2-ethoxyethyl groups, acetoxymethyl groups, pivalo Yloxymethyl group, 1-pivaloyloxyethyl group An ester with a lower alkanoyloxy lower alkyl group, an ester with a lower alkoxycarbonyl lower alkyl group such as a methoxycarbonylmethyl group or isopropoxycarbonylmethyl group, an ester with a carboxy lower alkyl group such as a carboxymethyl group, 1- (ethoxy Carbonyloxy) ethyl group, ester with lower alkoxycarbonyloxy lower alkyl group such as 1- (cyclohexyloxycarbonyloxy) ethyl group, ester with carbamoyloxy lower alkyl group such as carbamoyloxymethyl group, ester with phthalidyl group, And esters with a (5-substituted-2-oxo-1,3-dioxol-4-yl) methyl group such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group It is done.

  “Treatment agent” means a drug provided for the purpose of treatment and / or prevention against various diseases.

  In order to disclose the compound according to the present invention more specifically, the various symbols used in formula (I) and the like will be described in more detail by giving preferred specific examples.

R ¹ and R ² are each independently substituted with a substituent selected from the group consisting of a hydrogen atom, a cyclo-lower alkyl group, an aryl group, a heteroaryl group, or a cyclo-lower alkyl group, an aryl group, and a heteroaryl group. And the cyclo-lower alkyl group, aryl group and heteroaryl group are each independently composed of a halogen atom, a lower alkyl group, a halo-lower alkyl group and a lower alkoxy group. It may be substituted with a substituent selected from the group.

As the cyclo lower alkyl group for R ¹ or R ² , for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like are preferable.

As the aryl group for R ¹ or R ² , for example, a phenyl group is preferable.

As the heteroaryl group for R ¹ or R ² , for example, a pyridyl group is preferable.

The “lower alkyl group optionally substituted by a substituent selected from the group consisting of a cyclo-lower alkyl group, an aryl group and a heteroaryl group” for R ¹ or R ² is the unsubstituted lower alkyl group, or It means the lower alkyl group having a substituent at any substitutable position, and the substituent is the same or different from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group, preferably one or more, preferably One can be selected.

  The cyclo-lower alkyl group for the substituent is, for example, preferably a cyclopentyl group, a cyclohexyl group.

  The aryl group for the substituent is, for example, preferably phenyl.

  The heteroaryl group for the substituent is, for example, preferably a furyl group, a pyridyl group.

  Suitable examples of the substituent include a phenyl group and a pyridyl group.

As the “lower alkyl group” of the lower alkyl group which may have the above substituent of R ¹ or R ² , for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like are preferable. .

  The cyclo-lower alkyl group, aryl group and heteroaryl group are each independently substituted at any position where substitution is selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group and a lower alkoxy group It may be substituted by a group, and the substituents may be the same or different and can be selected from 1 or 2 and preferably 1 or 2.

  The halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.

  The lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.

  The halo-lower alkyl group for the substituent is, for example, preferably a difluoromethyl group, a trifluoromethyl group.

  The lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.

  As the substituent, for example, a halogen atom, a lower alkoxy group and the like are preferable.

Therefore, as R ¹ , for example, a hydrogen atom, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, methyl group, ethyl group, propyl group , Isopropyl group, butyl group, benzyl group, phenethyl group, furfuryl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl, 4-methylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethylphenyl group, 2-methoxyphenyl group 3-methoxyphenyl group, 4-methoxyphenyl group, 2-fluoro Robenzyl group, 2-chlorobenzyl group, 4-fluorobenzyl group, 4-chlorobenzyl group, 3,4-dimethoxyphenethyl group, and the like. Among them, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, propyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4-chlorophenyl group or 3-methoxyphenyl group, or phenyl group, benzyl group, 3-chlorophenyl group, 4-fluorophenyl group or 4- A methoxyphenyl group and the like are preferable, and a cyclohexyl group, a phenyl group and the like are particularly preferable.

As R ² , for example, a hydrogen atom, a methyl group and the like are preferable, and a hydrogen atom is particularly preferable.

R ⁴ and R ⁵ each independently represents a lower alkyl group, a cyclo lower alkyl group, an aryl group or an aralkyl group, or R ⁴ and R ⁵ together with an adjacent carbon atom together with a cyclo lower alkylidene Each of the cyclo-lower alkyl group, cyclo-lower alkylidene group, aryl group or aralkyl group independently represents a halogen atom, a lower alkyl group, or a halo-lower alkyl group. And a substituent selected from the group consisting of lower alkoxy groups.

As the lower alkyl group for R ⁴ or R ⁵ , for example, a methyl group, an ethyl group, a propyl group and the like are preferable, and a methyl group is particularly preferable.

As the cyclo lower alkyl group for R ⁴ or R ⁵ , for example, cyclobutyl, cyclopentyl group, cyclohexyl group and the like are preferable.

As the aryl group for R ⁴ or R ⁵ , for example, a phenyl group and the like are preferable.

As the aralkyl group for R ⁴ or R ⁵ , for example, a benzyl group and the like are preferable.

As the cyclo-lower alkylidene group in the case where R ⁴ and R ⁵ “form a cyclo-lower alkylidene group together with adjacent carbon atoms”, for example, a 1,1-cyclobutylidene group and the like are preferable.

  The cyclo lower alkyl group, cyclo lower alkylidene group, aryl group or aralkyl group are each independently substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group. The substituents may be the same or different and may be selected from 1 or 2 and preferably 1 or 2.

  The halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.

  The lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.

  The halo-lower alkyl group for the substituent is, for example, preferably a difluoromethyl group, a trifluoromethyl group.

  The lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.

  As the substituent, for example, a halogen atom, a lower alkoxy group and the like are preferable.

As a preferred embodiment of R ⁴ and R ⁵ , when both are lower alkyl groups, more preferably both are methyl groups, or R ⁴ and R ⁵ together are a cyclo lower alkylidene group together with adjacent carbon atoms, more preferably May be used to form a 1,1-cyclobutylidene group or the like.

R ⁶ represents a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group or a lower alkoxy lower alkyl group.

The lower alkyl group for R ⁶ is, for example, preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and particularly preferably a methyl group.

The halo-lower alkyl group for R ⁶ is, for example, preferably a trifluoromethyl group.

The cyclo lower alkyl group for R ⁶ is, for example, preferably a cyclopropyl group.

The lower alkoxy lower alkyl group for R ⁶ is, for example, preferably a methoxymethyl group.

R ⁶ is preferably a lower alkyl group.

R ³ represents a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a lower alkyl group which may be substituted with a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group. The cyclo lower alkyl group, aryl group and heteroaryl group in R ³ are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group , Lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , _{^{-N (R 7) COR 8,}} -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R 8, _{^{SR 7, -SO 2 R 7,}} -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl And X represents —N (R ⁷ ) — or —O—.

The cyclo lower alkyl group for R ³ is, for example, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.

The aryl group for R ³ is preferably, for example, a phenyl group.

As the heteroaryl group for R ³ , for example, a pyridyl group, a 5-benzopyrazolyl group, a 6-benzopyrazolyl group and the like are preferable.

The “lower alkyl group optionally substituted by a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group” of R ³ is the above-mentioned unsubstituted lower alkyl group or a substitutable The lower alkyl group having a substituent at an arbitrary position is meant, and the substituent is the same or different from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group, and one or more, preferably one is selected. be able to.

  The cyclo-lower alkyl group for the substituent is, for example, preferably a cyclopentyl group, a cyclohexyl group.

  The aryl group for the substituent is, for example, preferably phenyl.

  The heteroaryl group for the substituent is, for example, preferably a furyl group, a pyridyl group.

  Suitable examples of the substituent include a phenyl group and a pyridyl group.

As the “lower alkyl group” itself of the lower alkyl group which may have the above substituent of R ³ , for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and the like are preferable.

The cyclo lower alkyl group, aryl group and heteroaryl group in R ³ are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group, lower alkoxy group, Halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, —CON (R ⁷ ) R ⁸ , —N (R ⁷ ) R ⁸ , —N (R ^{7) _{) COR 8, -N (R 7}} ) SO 2 R 8, -OCOR 7, -OCON (R 7) R 8, -SR 7, -SO 2 R 7, -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl And X represents —N (R ⁷ ) — or —O—.

  The halogen atom for the substituent is, for example, preferably a fluorine atom, a chlorine atom.

  The lower alkyl group for the substituent is, for example, preferably a methyl group, an ethyl group.

  The halo-lower alkyl group for the substituent is, for example, preferably a difluoromethyl group, a trifluoromethyl group.

  The lower alkoxy group for the substituent is, for example, preferably a methoxy group, an ethoxy group.

  The halo lower alkoxy group for the substituent is, for example, preferably a trifluoromethoxy group.

  The cyclo-lower alkyl group for the substituent is, for example, preferably a cyclopentyl group, a cyclohexyl group.

  The aryl group for the substituent is, for example, preferably a phenyl group.

  The heteroaryl group for the substituent is, for example, preferably a pyridyl group.

  The aryloxy group for the substituent is, for example, preferably a phenoxy group.

  The aralkyl group for the substituent is, for example, preferably a benzyl group.

^{-CON (R 7) R 8,} -N (R 7) R 8, -N (R 7) COR 8, -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R 8 _{^{, -SR 7, -SO 2 R 7}} , -SO 2 N (R 7) R 8, or

R ⁷ and R ⁸ of the group represented by each independently represent a hydrogen atom or a lower alkyl group; and X represents —N (R ⁷ ) — or —O—.

The lower alkyl group for R ⁷ or R ⁸ is, for example, preferably a methyl group, an ethyl group.

As the substituent, for example, a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, —SO ₂ N (R ⁷ ) R ^{8 and the} like are preferable.

Examples of R ³ include isopropyl group, cyclohexyl group, unsubstituted phenyl group, or halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo Lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , -N (R ⁷ ) COR ⁸ , -N (R ^{7 _{) SO 2 R 8, -OCOR 7}} , -OCON (R 7) R 8, -SR 7, -SO 2 R 7, -SO 2 N (R 7) R 8 and,

A phenyl group substituted with 1 or 2 substituents selected from the group consisting of and the like is preferred, and in particular, a halogen atom, a cyano group, a lower alkyl group, a halo lower alkyl group, a lower alkoxy group, a halo lower alkoxy group, A phenyl group substituted with one or two substituents independently selected from —SO ₂ N (R ⁷ ) R ^{8 and the} like is preferable.

Therefore, more specifically, as R ³ , for example, isopropyl group, cyclohexyl group, phenyl group, 5-benzopyrazolyl group, 6-benzopyrazolyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4 -Difluorophenyl group, 3,5-difluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 4-nitrophenyl group, 3-cyanophenyl group, 4 -Cyanophenyl group, 3-methylphenyl group, 4-methylphenyl group, 3,5-dimethylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 4-tert-butylphenyl group, 3-trifluoromethyl Phenyl group, 4-trifluoromethylphenyl group, 2-methoxyphenyl group, 3 Methoxyphenyl group, 4-methoxyphenyl group, 4-isopropoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-carboxyphenyl group, 4-cyclohexylphenyl group, 4-biphenylyl group, 4-benzylphenyl group, 4- Phenoxyphenyl group, 4-carbamoylphenyl group, 4-methylcarbamoylphenyl group, 4-dimethylcarbamoylphenyl group, 4-aminophenyl group, 4-methylaminophenyl group, 4-dimethylaminophenyl group, 4-acetylaminophenyl group 4- (N-methylacetylamino) phenyl group, 4-methylsulfonylaminophenyl group, 4- (N-methylmethylsulfonylamino) phenyl group, 4-tert-butoxycarbonyloxyphenyl group, 4-dimethylcarbamoyloxyphenyl Group, - methylthiophenyl group, 4-methylsulfonylphenyl group, 3-aminosulfonylphenyl group, 4-aminosulfonylphenyl group, 4-methylsulfonylphenyl group, or the formula

And the like are preferable. Among them, phenyl group, 4-fluorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-cyanophenyl group, 4-methylphenyl group, 4-isopropylphenyl group, 4-tert-butylphenyl group, 4-trifluoromethylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-biphenylyl group, 4-amino A sulfonylphenyl group, a 4-methylsulfonylphenyl group, and the like are preferable.

As a preferable aspect of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , for example, R ² is a hydrogen atom, R ³ is a phenyl group, and R ⁴ , R ⁵ and R ⁶ are methyl groups. In this case, it is preferable that R ¹ is a suitable group described above. Further, as other preferred embodiments of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ , for example, R ¹ is a suitable group described above, R ² is a hydrogen atom, R ⁴ , R ⁵ and R ⁶ are methyl groups, and R ³ is a phenyl group substituted with a suitable group described above.

Among the compounds represented by the general formula (I), R ² is a hydrogen atom, R ³ is a phenyl group, R ⁴ , R ⁵ and R ⁶ are methyl groups, and R ¹ is an n-butyl group, phenyl Group, 4-fluorophenyl group, 3-chlorophenyl group, 3,4-dichlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethylphenyl group, 4-methoxyphenyl group, furfuryl group , A benzyl group, a phenethyl group, a 4-fluorobenzyl group, a 2-chlorobenzyl group or a 3,4-dimethoxyphenethyl group are known compounds, for example, as a commercially available compound of [ChemBridge, R1 = phenyl group]. (Catalog number: 7904749).

  On the other hand, the general formula (Ia)

[Where:
R ^1a and R ^2a are each independently substituted with a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group, and a heteroaryl group. Means an optionally substituted lower alkyl group;
R ^4a and R ^5a each independently represents a lower alkyl group, a cyclo lower alkyl group, an aryl group or an aralkyl group, or R ^4a and R ^5a together represent a cyclo lower alkylidene together with an adjacent carbon atom. May form a group;
R ^6a means a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group or a lower alkoxy lower alkyl group; the cyclo lower alkyl group, cyclo lower alkylidene group, aryl group, aralkyl group and heteroaryl group are each independently And may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ^3a represents a lower alkyl group which may be substituted with a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group. The cyclo lower alkyl group, aryl group and heteroaryl group in R ^3a are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group , Lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , _{^{-N (R 7) COR 8,}} -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R _{^{, -SR 7, -SO 2 R 7}} , -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl And X represents —N (R ⁷ ) — or —O— (wherein R ^2a is a hydrogen atom, R ^3a is a phenyl group, and R ^4a , R ^5a and R ^6a are methyl groups). R ^1a is n-butyl group, phenyl group, 4-fluorophenyl group, 3-chlorophenyl group, 3,4-dichlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethyl. Phenyl group, 4-methoxyphenyl group, furfuryl group, benzyl group, phenethyl group, 4-fluorobenzyl group, 2-chlorobenzyl group or 3,4-dimethoxyphenethyl group. The compound represented by the taste not)] are novel compounds not described in literature, those which are created by the present inventors.

In the compound of the general formula (Ia), preferred embodiments of R ^1a , R ^2a , R ^3a , R ^4a , R ^5a, and R ^6a are those of the general formula (I) except for the case where they correspond to the known compounds R ^1, the same as the preferred embodiment of ^{R 2, R 3, R 4} , R 5 and ^{R 6.} Among them, R ^1a is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, propyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4-chlorophenyl group or 3-methoxyphenyl group. Is preferred, and more preferred is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

  “Any substitutable position” means a hydrogen atom that can be chemically substituted on a carbon atom, nitrogen atom, oxygen atom and / or sulfur atom, and is chemically stable as a result of the substitution. Represents the position to give the compound.

  The compounds according to the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituents or the salt form. Such compounds include all these stereoisomers, tautomers and mixtures thereof.

  The present invention includes various crystals, amorphous, salts, hydrates and solvates of the compounds according to the present invention.

  Furthermore, prodrugs of the compounds according to the invention also belong to the scope of the invention. In general, such prodrugs are functional derivatives of the compounds of the present invention that can be readily converted into the required compounds in vivo. Therefore, in the method for treating various diseases according to the present invention, the term “administration” refers not only to the administration of the specified compound but also to the administration of a compound that is converted into the specified compound in vivo after being administered to a patient. including. Conventional means for selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985, etc., the entire description of which is hereby incorporated by reference. Metabolites of these compounds include active compounds produced by placing the compounds of the present invention in a biological environment and are within the scope of the present invention.

Specific examples of the compound represented by the general formula (I), a salt or an ester thereof include, for example, the compound described in the production examples, a salt or an ester thereof, and among others, 3- (2,5-dihydro-3 -Methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl-3-trifluoromethyl-1H-indole- 2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenylmethyl -3-trifluoromethyl-1H-indole-2,4-dione,
1- (4-Fluorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (4-methoxyphenyl) -6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
1- (3-Chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
1- (4-Chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (3-methoxyphenyl) -6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1,6,6-trimethyl-3- Trifluoromethyl-1H-indole-2,4-dione,
1-ethyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-propyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1-isopropyl-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclopropyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl -3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclobutyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclopentyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclohexyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (2 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (3 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (4 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione,
3- (3-Ethyl-2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (3-Cyclopropyl-2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl -3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-5-oxo-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- Phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (3-Chlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl- 1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Chlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl- 1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-1- (2-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-dihydro-1- (3-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-1- (4-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -1-phenyl-3,5,6,7-tetrahydro-6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6-methyl-1-phenyl-3- Trifluoromethyl-1H-indole-2,4-dione,
3 ′-(2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -1′-phenyl-3′-trifluoromethyl-3 ′, 7′-dihydro Spiro [cyclobutane-1,6′-indole] -2 ′, 4 ′ (1′H, 5′H) -dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Fluorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Cyanophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-1- (4-isopropylphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-1- (4-methylphenyl) -5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Aminosulfonylphenyl) -2,5-dihydro-3-trifluoromethyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6 6-dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-tert-Butylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-cyclohexylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Benzylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-dihydro-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-phenoxyphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (biphenyl-4-yl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (3,5-Dichlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione, or 3- [2,5-dihydro-3-methyl- (4-methylsulfonylphenyl) -5-oxo-1- 1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione or a salt thereof is preferable. It is.

In addition, 3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- Phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenylmethyl -3-trifluoromethyl-1H-indole-2,4-dione,
1- (4-Fluorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (4-methoxyphenyl) -6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione, and 1- (3-chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl -1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione is a known compound.

  Next, the manufacturing method of the compound based on this invention is demonstrated.

  Compound (I) according to the present invention can be produced, for example, by the following production method or the method shown in Production Examples / Reference Examples. However, the production method of the compound (I) according to the present invention is not limited to these reaction examples.

Manufacturing method 1
Formula (II)

[Wherein R ¹ , R ⁴ and R ⁵ have the above-mentioned meanings] and a general formula (III)

[Wherein R ^a represents an ester residue, and R ^3p is selected from the group consisting of a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a cyclo lower alkyl group, an aryl group, and a heteroaryl group. Lower cyclo group optionally substituted by a substituent, wherein the cyclo lower alkyl group, aryl group and heteroaryl group in R ³ are each independently unsubstituted or halogen atoms, Nitro group, cyano group, lower alkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, optionally protected carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl Group, ^-CON ( ^R7ap ) ^R8ap , -N ( ^R7ap ) ^R8ap , -N ( ^R7ap ) C _{^{OR 8, -N (R 7ap)}} SO 2 R 8, -OCOR 7, -OCON (R 7ap) R 8ap, -SR 7bp, -SO 2 R 7, -SO 2 N (R 7ap) R 8ap, and

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl R ^7ap and R ^8ap each independently represent an amino or imino protecting group, a hydrogen atom or a lower alkyl group; R ^7bp represents a thiol protecting group, a hydrogen atom or a lower alkyl group X represents —N (R ^7ap ) — or —O—; R ⁶ has the above-mentioned meaning].
Formula (IV)

[Wherein R ¹ , R ^3p , R ⁴ , R ⁵ and R ⁶ have the above-mentioned meanings], and when the compound (IV) has a protecting group, the protecting group is removed. According to general formula (I-1)

[Wherein R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ have the above-mentioned meanings] can be produced.

This production method is a method for producing a compound represented by general formula (I) wherein R ² is a hydrogen atom, that is, a compound represented by general formula (I-1).

The ester residue represented by ^Ra is not particularly limited as long as it can be used in a so-called condensation reaction in the field of organic chemistry and does not adversely affect the reaction. For example, a methyl group, an ethyl group, Examples include lower alkyl groups such as propyl group, isopropyl group, butyl group, sec-butyl group, and tert-butyl group; aryl groups such as phenyl group and tolyl group; aralkyl groups such as benzyl group, and the like. preferable.

  In the above reaction, when an amino group, imino group, mercapto group, carboxyl group, etc. that are not involved in the reaction are present in the reactant, the amino group, imino group, mercapto group, carboxyl group is suitably an amino group or imino group. The reaction is carried out after protection with a protecting group for thiol, a protecting group for thiol or a protecting group for carboxyl, and the protecting group can be removed after the reaction.

  Examples of the “protecting group for amino group or imino group” include benzyl group, p-methoxybenzyl group, 3,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group and the like. Aralkyl group; for example, lower alkanoyl group such as formyl group, acetyl group, propionyl group, butyryl group, pivaloyl group; for example, benzoyl group; for example, arylalkanoyl group such as phenylacetyl group, phenoxyacetyl group; for example, methoxycarbonyl group, ethoxycarbonyl group Lower alkoxycarbonyl groups such as propyloxycarbonyl group and tert-butoxycarbonyl group; for example, aralkyloxycarbonyl such as benzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group and phenethyloxycarbonyl group ; Such as trimethylsilyl group, and the like lower alkylsilyl group such as tert- butyldimethylsilyl group and the like, in particular an acetyl group, a pivaloyl group, a benzoyl group, an ethoxycarbonyl group, etc. tert- butoxycarbonyl group are preferred.

  Examples of the “thiol protecting group” include lower alkylsilyl groups such as trimethylsilyl group and tert-butyldimethylsilyl group; for example, lower alkoxymethyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group; for example, tetrahydropyranyl group; For example, trimethylsilylethoxymethyl group; for example, aralkyl groups such as benzyl group, p-methoxybenzyl group, 2,3-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, trityl group; for example, formyl group, acetyl group, etc. Acyl group, and the like. In particular, methoxymethyl group, tetrahydropyranyl group, trityl group, trimethylsilylethoxymethyl group, tert-butyldimethylsilyl group, acetyl group and the like are preferable.

  Examples of the “carboxyl-protecting group” include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and tert-butyl groups; lower haloalkyl groups such as 2,2,2-trichloroethyl groups; Lower alkenyl groups such as 2-propenyl group; for example, aralkyl groups such as benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, benzhydryl group, trityl group, etc., and particularly methyl group, ethyl group, tert-butyl Group, 2-propenyl group, benzyl group, p-methoxybenzyl group, benzhydryl group and the like are preferable.

  In the reaction of the compound represented by the general formula (II) and the compound represented by the general formula (III), the compound (III) is usually used in an equimolar to excess molar amount relative to 1 mol of the compound (II). Preferably it is carried out using equimolar to 1.5 molar.

  The reaction is usually carried out in an inert solvent, and examples of the inert solvent include toluene, benzene, methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and the like, or mixed solvents thereof. More preferably, chloroform or the like is suitable.

  The reaction temperature is usually from 0 ° C. to the boiling point of the solvent used in the reaction, preferably room temperature.

  The reaction time is usually 5 minutes to 7 days, preferably 2 hours to 24 hours.

  After the completion of the reaction, ordinary treatment can be performed to obtain a crude product of the compound represented by the general formula (IV). The compound represented by the general formula (IV) thus obtained is purified according to a conventional method, or without purification, the compound has an amino group, imino group, thiol and / or carboxyl group protecting group. When it has, the compound of general formula (I-1) can be manufactured by performing combining the removal reaction of the protective group of an amino group, imino group, thiol, and / or a carboxyl group suitably.

  The removal of the protecting group varies depending on the kind of the protecting group and the stability of the target compound (I). For example, the method described in the literature [Protective Groups in Organic Synthesis, T . W. According to Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto, for example, solvolysis using an acid or base, for example, 0.01 mole to large excess of acid, Preferably, trifluoroacetic acid, formic acid, hydrochloric acid or the like, or a method in which an equimolar or large excess base, preferably potassium hydroxide, calcium hydroxide or the like is allowed to act; Chemical reduction using a metal hydride complex or the like, or a palladium-carbon catalyst , Catalytic reduction using Raney nickel catalyst or the like.

  The compound of general formula (I-1) can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography and the like.

  These compounds can be converted into pharmaceutically acceptable salts by a conventional method, and conversely, conversion from a salt to a free compound can also be performed according to a conventional method.

Manufacturing method 2
Formula (IV)

[Wherein R ¹ , R ^3p , R ⁴ , R ⁵ and R ⁶ have the above-mentioned meanings], and the general formula (V)

[Wherein L represents a leaving group, and R ²⁰ represents a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group, and a heteroaryl group. A lower alkyl group which may be substituted; and the cyclo lower alkyl group, aryl group and heteroaryl group are each independently a halogen atom, lower alkyl group, halo lower alkyl group and lower alkoxy group. And may be substituted with a substituent selected from the group consisting of: a compound represented by the general formula (VI):

[Wherein R ¹ , R ²⁰ , R ^3p , R ⁴ , R ⁵ and R ⁶ have the above-mentioned meanings], and when the compound (VI) has a protecting group, By removing, general formula (I-2)

[Wherein R ¹ , R ²⁰ , R ³ , R ⁴ , R ⁵ and R ⁶ have the above-mentioned meanings] can be produced.

This production method is a method for producing a compound represented by general formula (I) wherein R ² is a group other than a hydrogen atom, that is, a compound represented by general formula (I-2).

  Examples of the leaving group represented by L include a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, an organic sulfonyl group such as a methylsulfinyl group, a methylsulfonyl group, an ethylsulfonyl group or a phenylsulfonyl group, or a methylsulfonyloxy group, Examples thereof include organic sulfonyloxy groups such as a trifluoromethylsulfonyloxy group and p-tolylsulfonyloxy group. For example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom is preferred.

  The reaction between the compound represented by the general formula (IV) and the compound represented by the general formula (V) is usually 0.5 mol to excess mol of compound (V) with respect to 1 mol of compound (IV). The reaction is preferably carried out using 2.0 to 5.0 mol.

  The reaction is usually carried out in an inert solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, dimethylformamide, etc. in the presence of a base such as sodium hydride, sodium amide, sodium alkoxide or the like, or, for example, methanol, ethanol, acetonitrile. In the presence of a base such as sodium hydroxide, potassium hydroxide or potassium carbonate.

  The reaction temperature is usually preferably from 0 ° C. to the boiling point of the solvent used for the reaction, and the reaction time is usually preferably from 1 hour to 48 hours.

  After the completion of the reaction, ordinary treatment can be performed to obtain a crude product of the compound represented by the general formula (VI). The compound represented by the general formula (VI) thus obtained is purified according to a conventional method, or without purification, the compound has an amino group, imino group, thiol and / or carboxyl group protecting group. When it has, the compound of general formula (I-2) can be manufactured by performing combining suitably the removal reaction of the protective group of an amino group, an imino group, a thiol, and / or a carboxyl group.

  Removal of the protecting group can be carried out in the same manner as described in the production method 1.

  The compound of general formula (I-2) can be easily isolated and purified by ordinary separation means. Examples of such means include solvent extraction, recrystallization, column chromatography, preparative thin layer chromatography and the like.

  These compounds can be converted into pharmaceutically acceptable salts by a conventional method, and conversely, conversion from a salt to a free compound can also be performed according to a conventional method.

  The compound represented by the general formula (IV) can be produced by the production method 1, and the compound represented by the general formula (IV) obtained in the step of the production method is purified or purified. And can be used as a raw material for this production method.

  The compound represented by the general formula (II), (III) or (V) is, for example, a commercially available product, a method described in the literature, a method according to these methods, or the following methods, production examples and reference examples. It can manufacture by combining suitably the method etc. to describe as needed.

Manufacturing method A

[Wherein R ¹ , R ⁴ and R ⁵ have the above-mentioned meanings]
Production method A is a method for producing a compound represented by formula (II).

  According to this production method, the compound represented by the general formula (II) can be produced by reacting the compound represented by the formula (1) with the compound represented by the formula (2).

  In this reaction, the reaction method of the condensation reaction of ketone carbonyl and primary amine well known per se in the field of organic chemistry can be applied. Usually, for example, methanol, ethanol, benzene, toluene, ethyl ether, The reaction is carried out by allowing the compound (2) to act in an equimolar to excess molar amount with respect to 1 mol of the compound (1) in an inert solvent such as tetrahydrofuran or a mixed solvent thereof.

  The reaction temperature is usually 0 ° C. to the boiling point of the solvent used for the reaction, preferably room temperature to 100 ° C.

  The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

  The compound represented by the general formula (1) or (2) may be a commercially available product, or may be produced by appropriately combining known methods, methods described in production examples, or methods based thereon as necessary. .

Manufacturing method B

[Wherein R ^b represents an ester residue, and R ^3p , R ⁶ and R ^a have the above-mentioned meanings]
This production method is a method for producing a compound represented by the general formula (III).

  According to this production method, the compound represented by the general formula (III) is represented by the formula (5) by reacting the compound represented by the formula (3) with the hydrazine derivative represented by the formula (4). The compound (7) can be produced by reacting the compound (5) with the compound (5) to produce a compound (7), and subjecting the compound (7) to an intramolecular dehydration reaction.

The ester residue represented by R ^b, can be mentioned the same groups as the ester residue R ^a in the production method 1, versa preferred group.

  The step of producing the compound represented by the formula (5) by reacting the compound represented by the formula (3) with the hydrazine derivative represented by the formula (4) is usually based on 1 mol of the compound (3). The hydrazine derivative (4) is used in an amount of 0.5 mol to excess mol, preferably equimolar to 3.0 mol.

  The reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, ethyl ether, methanol, ethanol, benzene, toluene, dimethylformamide, or a mixed solvent thereof is suitable. is there.

  The reaction temperature is usually 0 ° C. to the boiling point of the solvent used for the reaction, preferably room temperature to 100 ° C.

  The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

  The step of producing a compound represented by the formula (7) by reacting a compound represented by the formula (5) with a compound represented by the formula (6) is itself a well-known ketone in the field of organic chemistry. The reaction method of 1,2-addition reaction to carbonyl can be applied. Usually, 0.5 mol to excess mol, preferably equimolar to 3 mol of compound (6) is used per 1 mol of compound (5). Performed using 0.0 mole.

  The reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, ethyl ether, methanol, ethanol, benzene, toluene, dimethylformamide, or a mixed solvent thereof is suitable. is there.

  The reaction temperature is usually 0 ° C. to the boiling point of the solvent used for the reaction, preferably room temperature to 100 ° C.

  The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

  In the process of producing the compound represented by the formula (III) from the compound represented by the formula (7), a reaction method of an intramolecular dehydration reaction well known in the field of organic chemistry can be applied. Usually, it is carried out by allowing a suitable dehydrating agent to act on the compound (7).

  Examples of the dehydrating agent include thionyl chloride, hydrogen chloride, sulfuric acid, phosphorus pentoxide, polyphosphoric acid, p-toluenesulfonic acid, and the like, among which thionyl chloride is preferable.

  The reaction is usually carried out in an inert solvent. As the inert solvent, for example, chloroform, methylene chloride, pyridine, benzene, toluene and the like, or a mixed solvent thereof is suitable. In addition, depending on the dehydrating agent used in the reaction, the dehydrating agent can be used as a reactant and solvent.

  The reaction temperature is usually 0 ° C. to the boiling point of the solvent used for the reaction, preferably room temperature to 100 ° C.

  The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

(Alternative method)
The compound represented by the general formula (7) can also be produced by the following steps.

[Wherein R ^b , R ^3p , R ⁶ and R ^a have the above-mentioned meanings]
According to this production method, the compound (7) is obtained by reacting the compound represented by the formula (3) with the compound represented by the formula (6) to obtain a compound represented by the formula (8). ) Is allowed to act on the hydrazine derivative represented by the formula (4).

  The step of producing the compound represented by the formula (8) by reacting the compound represented by the formula (3) with the compound represented by the formula (6) is usually performed with respect to 1 mol of the compound (3). Compound (6) is used in an amount of 0.5 mol to excess mol, preferably equimolar to 3.0 mol.

  The reaction is usually carried out in an inert solvent, and as the inert solvent, for example, methylene chloride, chloroform, tetrahydrofuran, ethyl ether, methanol, ethanol, benzene, toluene, dimethylformamide, or a mixed solvent thereof is suitable. is there.

  The reaction temperature is usually 0 ° C. to the boiling point of the solvent used for the reaction, preferably room temperature to 100 ° C.

  The reaction time is usually 5 minutes to 7 days, preferably 30 minutes to 24 hours.

  The step of producing compound (7) by reacting compound (8) with a hydrazine derivative represented by formula (4) is represented by formula (4) and compound represented by formula (3) in the above production method. It can carry out similarly to the process of manufacturing the compound represented by Formula (5) by making a hydrazine derivative react. That is, the hydrazine derivative (4) is usually used in an amount of 0.5 mol to excess mol, preferably equimolar to 3.0 mol with respect to 1 mol of the compound (8).

  In addition, the reaction conditions such as the solvent used in the reaction, the reaction temperature, and the reaction time are the same as in the step of producing the compound (3) to (5).

  In addition, the compound represented by the general formula (3), (4) or (6) may be a commercially available product, or may be produced by appropriately combining known methods, methods described in production examples, or methods based thereon as necessary. can do.

The usefulness of the compound according to the present invention as a medicine is proved, for example, in the following pharmacological test examples.
Pharmacological test example 1 (LCE enzyme activity inhibition test)
The test compound was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM and further diluted with DMSO to prepare a 1000-fold concentrated solution of the evaluation concentration. The LCE enzyme activity inhibition test was performed by improving the method of Moon (J. Biol. Chem., 276, 45358-45366 (2001)). That is, after adding diluted test compound to a 96-well assay plate (Corning, 96-well assay block) 1.0 μL per well, 50 μL phosphate buffer solution (100 mM potassium phosphate buffer solution (pH 6.5)) , 25 μL of substrate solution (100 mM potassium phosphate buffer (pH 6.5), 4.0 μM rotenone, 80 μM fatty acid-free bovine serum albumin, 160 μM palmitoyl CoA, 80 μM malonyl CoA, 3.5 μM [ ¹⁴ C] -malonyl CoA ( 1.92 GBq / mmol, manufactured by Amersham)) is added to each well, and 25 μL of enzyme solution (100 mM potassium phosphate buffer (pH 6.5), 100 μg / mL human LCE) is added and the top of the plate is sealed with a seal And mild at 37 ° C for 90 minutes It was incubated with stirring crab shaking. Thereafter, 100 μL of 5N HCl was added to each well and the assay plate was agitated at room temperature for 5 minutes to stop the enzyme reaction and hydrolyze acyl CoA. Thereafter, the enzyme reaction solution in each well was adsorbed to each well of a 96-well GF / C filter plate (PerkinElmer Unifilter 96GF / C) in which water was passed in advance, and each well was washed with water to remove the non-adsorbed solution. After removing the malonyl CoA, the GF / C filter plate was dried at 50 ° C. for 60 minutes. Thereafter, 30 μL of scintillator (PerkinElmer micro scintillation 0) was added to each well to seal the upper part of the plate, and the immobilized [ ¹⁴ C] radioactivity was measured with a microplate scintillation counter (PerkinElmer top count) as enzyme activity. . The enzyme inhibitory activity of human LCE by the test compound was calculated using the radioactivity in a well containing DMSO not containing the test compound as a control.

  When the activity of the compounds of the present invention was examined using this assay, these compounds inhibited the activity of human LCE. The results are shown in Table 1.

Pharmacological Test Example 2 (Intracellular LCE activity inhibition test)
The mouse liver-derived cultured cell line H2.35 cells were maintained in DMEM (GIBCO) supplemented with 4% fetal calf serum and 200 nM dexamethasone, and cultured at 33 ° C. under 5% CO ₂ . About 2.5 × 10 ⁵ H2.35 cells were dispensed into a 24-well cell culture plate (Corning, 24-well cell culture cluster) and cultured overnight at 33 ° C. under 5% CO _2. A test compound dissolved in sulfoxide (DMSO) was added to an evaluation concentration. After culturing at 33 ° C. for 1 hour under 5% CO ₂ , [ ¹⁴ C] -palmitoyl CoA (2.13 GBq / mmol, manufactured by PerkinElmer) was added to each well, and further 4 at 33 ° C. under 5% CO _2. After time incubation, each well was washed with ice-cold phosphate buffered saline and the reaction was stopped by adding 250 μL of 2M sodium hydroxide. Thereafter, the reaction solution in each well was transferred to a glass test tube, incubated at 70 ° C. for 1 hour, 100 μL of 5N hydrogen chloride solution was added, fatty acids were extracted with petroleum ether, and then [ ¹⁴ C] by radio HPLC. The amount of labeled fatty acid was measured, and the quantitative ratio (C18 / C16 ratio) of 18 carbon chains and 16 carbon chains was calculated. The intracellular LCE inhibitory activity of the test compound was calculated using the C18 / C16 ratio in a well containing DMSO not containing the test compound as a control.

  When the activities of the compounds of the present invention were examined using this assay, these compounds inhibited intracellular LCE activity. The results are shown in Table 2.

The compound represented by the general formula (I) or (Ia) can be administered orally or parenterally, and by formulating it into a form suitable for such administration, for example, hypertension, angina Disease, heart failure, myocardial infarction, stroke, lameness, diabetic nephropathy, diabetic retinopathy, decreased vision, electrolyte abnormalities, arteriosclerosis and other cardiovascular diseases such as bulimia and diabetic neuropathy Diseases such as metabolic syndrome, obesity, diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceremia, dyslipidemia, nonalcoholic fatty liver, abnormal hormone secretion, gout, fatty liver Metabolic diseases such as menstrual disorders, reproductive system diseases such as sexual dysfunction, liver dysfunction, pancreatitis, cholecystitis, gastrointestinal tract diseases such as gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), sleep Respiratory diseases such as respiratory syndrome, can be subjected infectious diseases caused by bacteria, fungi, parasites, malignant neoplasms, arthritis, as a treatment agent, such as inflammatory diseases such as skin ulcers.

  One aspect of the present invention requires a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. It is to provide a method for the treatment or prevention of a disease, illness or condition resulting from modulation of LCE comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. Treatment of metabolic syndrome, fatty liver, hyperlipidemia, dyslipidemia, non-alcoholic fatty liver, obesity, diabetes, bulimia, malignant neoplasm or infectious disease Is to provide preventive measures.

  Another aspect of the present invention is to provide a therapeutically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. It is to provide a therapeutic method for metabolic syndrome, fatty liver, hyperlipidemia, obesity, diabetes, bulimia, malignant neoplasms or infectious diseases.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. To provide a method for treating or preventing diabetes, comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. To provide a method for treating or preventing obesity comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. Overeating, bulimia, high blood pressure, elevated plasma insulin concentration, insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, renal cancer, deformity Arthropathy, obstructive sleep apnea, heart disease, abnormal heart rhythm, arrhythmia, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary, craniopharyngioma, metabolic syndrome, insulin Resistance syndrome, sexual and reproductive dysfunction, infertility, hypogonadism, hirsutism, obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), inflammation, systemic vasculitis, arteriosclerosis , High Sterolemia, hyperuricemia, low back pain, inflammation, systemic vasculitis, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, constipation, irritable bowel syndrome, inflammatory bowel The object is to provide a method for treating or preventing obesity-related diseases selected from the group consisting of syndrome, cardiac hypertrophy and left ventricular hypertrophy.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. It is intended to provide a method for treating or preventing hyperlipidemia or dyslipidemia comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. It is to provide a method of caloric intake comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. It is to provide a method for reducing food intake, comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. Providing a method of increasing satiety, comprising administering to a subject.

  Another aspect of the present invention is the need for a therapeutically or prophylactically effective amount of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof. It is to provide a method for reducing appetite, comprising administering to a subject.

  In addition, the present invention treats compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, with other drugs known to be useful for the treatment or prevention of the condition. The present invention relates to a method for treating or preventing obesity comprising administering in combination with a therapeutically or prophylactically effective amount.

  In addition, the present invention treats compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, with other drugs known to be useful for the treatment or prevention of the condition. The present invention relates to a method for treating or preventing diabetes comprising administering in combination with an effective or prophylactically effective amount.

  In addition, the present invention treats compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, with other drugs known to be useful for the treatment or prevention of the condition. The present invention relates to a method for treating or preventing hyperlipidemia or dyslipidemia comprising administration in combination with a therapeutically or prophylactically effective amount.

  Another aspect of the present invention is a pharmaceutical composition comprising the compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Is to provide.

  Yet another aspect of the present invention relates to a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

  Yet another aspect of the present invention is a compound (I) or (I-) according to the present invention for the manufacture of a medicament useful for the treatment, prevention, or suppression of a disease caused by LCE in a subject in need thereof. a) or the use of pharmaceutically acceptable salts thereof.

  Yet another aspect of the invention is the metabolic syndrome, hyperlipidemia, dyslipidemia, non-alcoholic fatty liver, obesity, diabetes, bulimia, malignant neoplasm or infection of the subject in need thereof It relates to the use of a compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful for the treatment or prevention of sexually transmitted diseases.

  Yet another aspect of the present invention is the compound (I) or (Ia) according to the present invention for the manufacture of a medicament useful for the treatment or prevention of obesity in a subject in need thereof, or they The use of a pharmaceutically acceptable salt.

  Yet another aspect of the present invention is a compound (I) or (Ia) according to the present invention for the manufacture of a medicament useful for the treatment or prevention of diabetes in a subject in need thereof, It relates to the use of pharmaceutically acceptable salts.

  Yet another aspect of the present invention is a compound (I) or (1) according to the present invention for the manufacture of a medicament useful for the treatment or prevention of hyperlipidemia or dyslipidemia in a subject in need thereof. It relates to the use of Ia), or a pharmaceutically acceptable salt thereof.

In still another aspect of the present invention, there is provided a therapeutically effective amount of the compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, an insulin sensitizer, Insulin analogs, sulfonylureas, α-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP-4 or DP-IV) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, HMG-CoA reductase inhibitors, serotonin -Like substance, β3-adrenergic receptor agonist, neuropeptide Y1 antagonist, neuropeptide Y2 agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist Medicine, melanocortin 4 receptor agonist, bombesin receptor subtype 3 agonist, gray Down antagonist, PYY, to the use of PYY _3-36 and drug or therapeutically effective amount of their pharmaceutically acceptable salts are selected from the group consisting of NK-1 antagonist, you need them The present invention relates to the use for the manufacture of a medicament useful for the treatment, management or prevention of obesity, diabetes, diabetes-related diseases or obesity-related diseases in a subject.

In still another aspect of the present invention, there is provided a therapeutically effective amount of the compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, an insulin sensitizer, Insulin analogs, sulfonylureas, α-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP-4 or DP-IV) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, HMG-CoA reductase inhibitors, serotonin -Like substance, β3-adrenergic receptor agonist, neuropeptide Y1 antagonist, neuropeptide Y2 agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist Medicine, melanocortin 4 receptor agonist, bombesin receptor subtype 3 agonist, gray Down antagonist, PYY, PYY _3-36 and NK-1 drugs selected from the group consisting of antagonist or a therapeutically effective amount of obesity their pharmaceutically acceptable salts, diabetes, diabetes-related diseases or Use for the manufacture of a medicament for use in the treatment or prevention of obesity-related diseases, comprising an effective amount of compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, It relates to the simultaneous or separate use of an effective amount of the above drugs.

In still another aspect of the present invention, there is provided a therapeutically effective amount of the compound (I) or (Ia) according to the present invention, or a pharmaceutically acceptable salt thereof, an insulin sensitizer, Insulin analogs, sulfonylureas, α-glucosidase inhibitors, dipeptidyl peptidase 4 (DPP-4 or DP-IV) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, HMG-CoA reductase inhibitors, serotonin -Like substance, β3-adrenergic receptor agonist, neuropeptide Y1 antagonist, neuropeptide Y2 agonist, neuropeptide Y5 antagonist, pancreatic lipase inhibitor, cannabinoid CB1 receptor antagonist or inverse agonist, melanin-concentrating hormone receptor agonist Medicine, melanocortin 4 receptor agonist, bombesin receptor subtype 3 agonist, gray Down antagonist, PYY, consisting PYY _3-36 and drug or therapeutically effective amount of their pharmaceutically acceptable salts are selected from the group consisting of NK-1 antagonist, obesity, diabetes, diabetes associated It relates to products as a combination for simultaneous, separate or sequential use of diseases or obesity related diseases.

  In yet another aspect of the present invention, there is provided a therapeutically effective amount of compound (I) or (Ia) or a pharmaceutically acceptable salt thereof according to the present invention, simvastatin, mevastatin, ezetimibe, Use of a therapeutically effective amount of a drug selected from the group consisting of atorvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa (trade name) and phentermine, or a pharmaceutically acceptable salt thereof, The invention relates to the above use for the manufacture of a medicament useful for the treatment, management or prevention of obesity, diabetes, diabetes-related diseases or obesity-related diseases in a subject in need.

  When the compound according to the present invention is used clinically, it can be administered after various preparations by adding a pharmaceutically acceptable additive according to the administration form. As the additive at that time, various additives that are usually used in the pharmaceutical field can be used. For example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, methylated cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, Corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, Hardened castor oil, polyvinylpyrrolidone, magnesium stearate, palmitooleic acid, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, Pyrene glycol, polyalkylene glycol, cyclodextrin or hydroxypropyl cyclodextrin and the like.

  Examples of dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or glucose solution as necessary, and buffering agents and preservatives may be added.

  The compounds according to the present invention are effective for animals and plants including humans or other mammals that require treatment with the compounds. The mammal is preferably a human and may be male or female. Examples of mammals other than humans include pets such as dogs and cats. The compound according to the present invention is also effective against obesity such as dogs and cats or diseases related to obesity. Whether or not treatment with the compound is required can be readily determined by a regular physician, veterinarian or clinician.

  When the compound according to the present invention is used, for example, in a clinical setting, the dose and the number of administrations vary depending on the sex, age, weight, degree of symptoms of the patient, and the type and range of the intended treatment effect. In the case of oral administration, 0.01 to 100 mg / kg, preferably 0.03 to 1 mg / kg per adult day, is divided into 1 to several times, and in the case of parenteral administration, 0.001 to 10 mg / kg. It is preferable to administer kg, preferably 0.001 to 0.1 mg / kg, more preferably 0.01 to 0.1 mg / kg divided into 1 to several times.

  For oral administration, 1.0-1000 mg of active ingredient, especially 1.0, 5.0, 10.0, 15.0, 20 to adjust the dosage to the condition of the patient being treated 0.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0 800.0, 900.0 and 1000.0 mg tablets containing 1000.0 mg of the active ingredient are preferred. The compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

  The compounds according to the invention are applied for the treatment or prevention of obesity and / or diabetes and / or hyperlipidemia and / or dyslipidemia and / or non-alcoholic fatty liver, or other diseases In this case, when the daily dose of the compound of the present invention is about 0.1 mg to about 100 mg per kg body weight of the animal, it is more preferable to administer a single dose or 2 to 6 divided doses per day, or gradually. Satisfactory results can generally be obtained when using a releasable formulation. For many large mammals, the total daily dose is from about 1.0 mg to about 1000 mg, preferably from about 1 mg to about 50 mg. For a 70 kg adult, the total daily dose will usually be from about 7 mg to about 350 mg. This dosage regimen can be adjusted to provide the best therapeutic effect.

  Ordinary physicians, veterinarians or clinicians can easily determine and handle the effective amount of drug needed to treat, prevent, prevent, inhibit or stop disease progression.

  These preparations can contain the compound according to the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight of the total drug. These formulations may also contain other therapeutically effective compounds.

  The compounds according to the present invention include cardiovascular diseases such as hypertension, angina pectoris, heart failure, myocardial infarction, stroke, lameness, diabetic nephropathy, diabetic retinopathy, vision loss, electrolyte abnormalities, arteriosclerosis, such as bulimia Central nervous system diseases such as diabetic neuropathy, eg metabolic syndrome, obesity, diabetes, insulin resistance, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, nonalcoholic fat Metabolic diseases such as liver, hormonal secretion abnormalities, gout, fatty liver, reproductive system diseases such as menstrual disorders, sexual dysfunction, liver dysfunction, pancreatitis, cholecystitis, gastrointestinal diseases such as gastroesophageal reflux, low obesity For treatment of respiratory diseases such as ventilation syndrome (Pickwick syndrome), sleep apnea syndrome, infectious diseases caused by bacteria, fungi, and parasites, malignant neoplasms, arthritis, inflammatory diseases such as skin ulcers, etc. Yes It can be used in combination with such other agents. The individual components of such a combination can be administered in divided or single formulations at different times or simultaneously during the treatment period. Thus, the present invention should be construed to include all simultaneous or timed administrations, and administration in the present invention should be construed as such. The range of combinations of the compounds of the present invention with other agents useful for the treatment of the above-mentioned diseases includes, in principle, combinations with any pharmaceutical preparations useful for the treatment of the above-mentioned diseases.

  Such combinations include combinations of the composition of the present invention not only with one other active substance, but also with two or more other active substances. There are many examples of combinations of the composition of the present invention with one, two or more activators selected from the above therapeutic agents. For example, for the purpose of treatment / management / prevention of metabolic syndrome, one, two or more activators selected from the composition of the present invention and a hyperlipidemic agent, a lipid-reducing agent and an anti-diabetic agent The combination with is beneficial. In particular, in addition to anti-diabetic drugs and / or anti-hyperlipidemic agents or lipid-reducing agents, compositions comprising anti-obesity agents and anti-hypertensive agents have a synergistic effect on the treatment, management or prevention of metabolic syndrome To do.

  Examples of drugs combined with this drug include ACAT inhibitor, α-procker, aldose reductase inhibitor, α-amylase inhibitor, angiotensin converting enzyme inhibitor, angiotensin receptor antagonist, anion exchange resin, appetite suppressant, antioxidant Agent, antiplatelet agent, beta blocker, biguanide agent, calcium antagonist, CB1 receptor inverse agonist / antagonist, CETP inhibitor, cholesterol absorption inhibitor, DGAT inhibitor, DP-IV inhibitor, diuretic, eicosapentaenoic acid , Endothelin antagonist, FLAP inhibitor, FXR modulator, ghrelin antagonist, GLP-1 agonist, GLP-1 secretion agent, glucagon antagonist, glucokinase activator, glucocorticoid receptor ligand, α-glycosidase inhibitor, GPAT inhibition Agent, histamine 3 receptor ligands, HMG-CoA reductase inhibitors, HSD inhibitors, insulin and its similar drugs, kinase inhibitors such as VEGF inhibitors and PDGF inhibitors, leptin, lipase inhibitors, 5-LO inhibitors, LXR ligands, Melanocortin agonist, MCH antagonist, MTTP inhibitor, orexin antagonist, opioid antagonist, neuropeptide Y antagonist, nicotinic acid agonist, PPAR ligand, PTP-1B inhibitor, SCD-1 inhibitor, serotonin transporter inhibitor, SGLT inhibitors, SUR ligands, thyroid hormone agonists, UCP activators, VPAC receptor agonists and the like.

  More specifically, examples of other active ingredients to be taken in combination with the composition according to the present invention and as separate or identical drug compositions include, but are not limited to:

(A) (1) Glitazones (for example, ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, turric, BRL49653, CLX-0921, 5-BTZD, etc.) and GW-0207 PPARγ agonists such as LG-100631, LY-300512, etc., (2) biguanides such as buformin, metformin, phenformin, etc., (3) protein tyrosine kinase-1B (PTP-1B) inhibitors, (4) Sulfonyuria such as acetohexamide, chlorpropamide, diabinase, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, glyquidone, glicoramide, tolazamide, and tolbutamide. (5) meglitinides such as repaglinide and nateglinide, (6) acarbose, adiposine, camiglibose, emiglitate, migitolitol, voglibose, pradimicin-Q, salvostatin, CKD-711, MDL-25, 637, MDL-73, Α-glucoside hydrolase inhibitors such as 945 and MOR14, (7) α-amylase inhibitors such as tendamistat, trestatin and Al-3688, (8) linoglylide, and insulin such as A-4166 (9) fatty acid oxidation inhibitors such as chromoxyl and etomoxil, (10) α2 antagonists such as midaglyzol, isagridol, deligridol, idazoxan, aeroxan and fluparoxane, (11) biota, LP-100, no Balapide, Insulin Detemir, Insulin Lispro, Insulin Glaldine, Insulin Zinc Suspension (Lente and Ultralente), Lys-Pro Insulin, GLP-1 (73-7) (Insulin Tropine), and GLP-1 (7-36) -NH ₂ Insulin or insulin analogues such as (12) JT-501 and farglitazar (GW-2570 / GI-262579), non-thiazolidinediones such as muraglitazar, muraglitazar, U.S. Pat. PPARα / δ dual agonists such as the compounds disclosed in US Pat. No. 6,414,002, (13) MK-0767 / KRP-297, CLX-0940, GW-1536, GW-1929, GW-2433, L-79449 PPARα / γ dual agonists such as LR-90 and SB219994, (14) other insulin sensitizers, (15) VPAC2 receptor agonists, (16) glucokinase activators, (17) sitagliptin (Januvia (trade name)), isoleucine thiazolidide (P32 / 98), NVP-DPP-728, vildagliptin (LAF237), P93 / 01, denagliptin (GSK823093), SYR322, RO0730699, TA-6666 and saxagliptin (BMS477118) D such as P-4 inhibitors, antidiabetic agents such as
(B) (1) Bile acid absorption inhibitors such as cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivatives of cross-linked dextran, Colestid (trade name), LoCholest (trade name), and Questran (trade name), 2) HMG-CoA reductase inhibitors such as atorvastatin, itavastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rivastatin, rosuvastatin, simvastatin and ZD-4522, (3) HMG-CoA synthase inhibitor, (4) stanol Esters, β-sitosterol, sterol glycosides such as chicueside, and cholesterol absorption inhibitors such as azetidinones such as ezetimibe, (5) abashimibe, eflucimibe, KY505, Acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitors such as MP797, (6) CETP inhibitors such as JTT705, torcetrapib, CP532, 632, BAY63-2149, SC591, SC795, (7) squalene synthase Inhibitors, (8) antioxidants such as probucol, (9) beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW7647 , BM170744, LY518673, and other fibric acid derivatives such as Atromid (trade name), Lopid (trade name), and Tricor (trade name), and PPARα agonists such as the compounds disclosed in International Patent Application Publication No. WO 97/36579 (10) FXR receptor modulators such as GW4064 and SR103912, (11) LXR receptor ligands such as GW3965, T901137, and XTCO179628, (12) lipoprotein synthesis inhibitors such as niacin, (13) renin-angiotensin System inhibitors, (14) PPARδ partial agonists, (15) bile acid reabsorption inhibitors such as BARI1453, SC435, PHA384640, S8921, AZD7706, (16) GW501516, GW590735, etc., and International Patent Application Publication WO97 / PPARδ agonists such as the compounds disclosed in 28149, (17) inhibitors of triglyceride synthesis, (18) microsomal triglycerides such as imputapide, LAB687, and CP346086. Transport (MTTP) inhibitor, (19) transcription modulator, (20) squalene epoxidase inhibitor, (21) low density lipoprotein (LDL) receptor inducer, (22) platelet aggregation inhibitor, (23) 5-LO Or a FLAP inhibitor, and
(24) a lipid reducing agent such as a niacin receptor agonist, and
(C) (1) diuretics such as thiazides including chlorthalidone, chlorthiazide, dichlorophenazide, hydroflumethiazide, indapamide, and hydrochlorothiazide, loop diuretics such as bumetanide, ethacrynic acid, furosemide, and tolsemide, amiloride , And aldosterone antagonists such as spironolactone and epilenone, (2) acebutolol, atenolol, betaxolol, bevantrol, bisoprolol, bopindolol, carteolol, carvedilol, ceriprolol, esmolol, indenolol , Metaprolol, nadolol, nebivolol, penbutolol, pindolol, propanolol, sotalol, tertatrol, chilisolol, and timoro (3) amlodipine, alanidipine, azelnidipine, varnidipine, benidipine, bepridil, sinaldipine, clevidipine, diltiazem, efonidipine, felodipine, galopamil, isradipine, rasidipine, lercandipine, lercanidipine, lercanidipine, , Nimodipine, nisoldipine, nitrendipine, manidipine, pranidipine, and calcium channel blockers such as verapamil, (4) benazepril, captopril, cilazapril, delapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, prilapril, prilapril Perindropril, quaanipril, spirapril, tenocapri Angiotensin-converting enzyme (ACE) inhibitors such as sulfato, trandolapril, and zofenopril; (5) neutral endopeptidase inhibitors such as omapatrirat, cadoxatril and equadotril, fosidetolyl, sampatotrirat, AVE7688, ER4030, (6) Endothelin antagonists such as bosentan, tezosentan, A308165, and YM62899, (7) Vasodilators such as hydralazine, clonidine, minoxidil, and nicotinyl alcohol (8) Candesartan, eprosartan, irbesartan, losartan, plato Angiotensin II receptor antagonists such as sultan, tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270, (9) Nip Α / β-adrenergic blockers such as dilol, arotinolol and amosulalol, (10) α1 blockers such as terazosin, urapidil, prazosin, bunazosin, trimazosin, doxazosin, naphthopidyl, indolamine, WHIP164 and XEN010, (11) Antihypertensive agents such as lofexidine, thiamenidine, moxonidine, rilmenidine, guanobenz and the like, (12) aldosterone inhibitors, and the like, and
(D) (1) 5HT (serotonin) transporter inhibitors such as paroxetine, fluoxetine, fenfluramine, fluvoxamine, sertraline, and imipramine, (2) NE (norepinephrine) transporters such as GW320659, despyramine, talspram, and nomifensine. Inhibitors, (3) rimonabant (Sanofisyn Labs), SR-147778 (Sanofisyn Labs), BAY65-2520 (Bayer), and SLV319 (Solvay); 5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736, 5,624,941 and 6,028,084, and WO96 / 33159, WO98 / 33765, WO98 / 43636, WO98 / 43635, WO01 / 09120, WO01 / 96330, WO98 / 31227, WO98 / 41519, WO98 / 37061, WO00 / 10967, WO00 / 10968, WO97 / 29079, WO99 / 02499 WO01 / 58869, WO02 / 076949, WO01 / 64632, WO01 / 64633, WO01 / 64634, WO03 / 006007, and WO03 / 007887, WO04 / 048317, WO05 / 000809, and EPO Application No. CB-1 (cannabininoindo-1 receptor) antagonists / antiagonists such as the compounds disclosed in EP-658546, EP656354, EP576357, (4) such as the drugs disclosed in WO01 / 87335, and WO02 / 08250 Ghrelin antagonist, (5) thioperamide, 3- (1H-imidazol-4-yl) propyl N- (4-pentenyl) carbamate, clobenpropit, iodophenpropit, imoproxyphan, GT2394 (Gliatec) And A331440, and the drug disclosed in WO 02/15905, and O- [3- (1H-imidazol-4-yl) propanol] carbamate (Kiec-Konowicz, K. et al., Pharmazie, 55: 349-). 55 (2 00)), piperidine-containing histamine H3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56: 927-32 (2001)), benzophenone derivatives and related compounds (Sase, A. et al., Arch. Pharm). (Weinheim) 334: 45-52 (2001)), substituted N-phenyl carbamates (Reidemeister, S. et al., Pharmazie, 55: 83-6 (2000)), and proxyphane derivatives (Sasse, A. et al.). et al., J. Med. Chem., 43: 3335-43 (2000)), (6) T-226296 (Takeda), SNP-7941 (Synaptic, Inc.) ), And WO01 / 82925, O01 / 87834, WO02 / 051809, WO02 / 06245, WO02 / 076929, WO02 / 076947, WO02 / 04433, WO02 / 51809, WO02 / 083134, WO02 / 094799, WO03 / 004027, and Japanese patent application numbers JP132226269, JP2004-139909 (7) MCH2R (melanin-concentrating hormone 2R) agonist / antagonist, (8) BIBP3226, 2- [1- (5-chloro- 3-isopropyloxycarbonylaminophenyl) ethylamino] -6- [2- (5-ethyl-4-methyl-1,3-thiazol-2-yl) ethyl] -4-morpholinopyridine, BIBO3304, LY-357897, CP-671906, and GI-264879A, and U.S. Pat. 6,001,836, and NPY1 (neuropeptide YY1) antagonists such as the drugs disclosed in WO96 / 14307, WO01 / 23387, WO99 / 51600, WO01 / 85690, WO01 / 85098, WO01 / 85173, and WO01 / 89528 (9) L-152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X, FR235, 208, FR-226928, FR240662, FR252384, 1229U91, GI-264879A, CGP71683A, LY-377897 LY366377, PD-160170, SR-120562A, SR-120919A, JCF-104, and H409 / 22, and U.S. Pat. 6,057,335, 6,043,246, 6,140,354, 6,166,038, 6,180,653, 6,191,160, 6,258,837, 6,313,298, 6, 337,332, 6,329,395, and 6,340,683, U.S. Pat. 6,326,375, 6,329,395, 6,337,332, 6,335,345, 6,388,077, 6,462,053, 6,649,624, 6,723,847, European patents No. EP-01010691, EP-010449970, and PCT International Patent Application Publication No. WO97 / 19682, WO97 / 20820, WO97 / 20821, WO97 / 20822, WO97 / 20823, WO98 / 27063, WO00 / 107409, WO00 / 185714, WO00 / 185730, WO00 / 64880, WO00 / 68197, WO00 / 69849, WO01 / 09120, WO01 / 14376, WO01 / 85714, WO01 / 85730, WO01 / 07409, WO01 / 02379, WO01 / 23388, WO01 / 33389, WO01 / 44201, WO01 / 62737, WO01 / 62738, WO01 / 09120, WO02 / 20488, WO02 / 22592, WO02 / 48152, WO02 / 49648, WO02 / 094989, WO02 / 09482 , WO03 / 014083, WO03 / 10191, WO03 / 092889, WO2004 / 002986, WO2004 / 031175 and Norman et al. , J .; Med. Chem. 43: 4288-4312 (2000), such as NPY5 (neuropeptide YY5) antagonists, (10) recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen). Leptins, (11) U.S. Pat. 5,552,524, 5,552,523, 5,552,522, 5,521,283, and PCT international patent no. Leptin derivatives such as WO96 / 23513, WO96 / 23514, WO96 / 23515, WO96 / 23516, WO96 / 23517, WO96 / 23518, WO96 / 23519, and WO96 / 23520, (12) nalmefene (Revex (trade name)), 3 Methoxynaltrexone, naloxone, and naltrexone, and opioid antagonists such as the compounds disclosed in WO00 / 21509, (13) SB-334867-A, and WO01 / 96302, WO01 / 68609, WO02 / 51232, WO02 / 51838, And orexin antagonists such as the compounds disclosed in WO 03/023561, (14) [D-Phe6, beta-Ala11, Phe13, Nle14] Bn (6-14) and [D-Phe , Phe13] Bn (6-13) propylamide, and Pept. Sci. 2002, Aug; 8 (8): 461-75, a BRS3 (bombesin receptor subtype 3) agonist, such as the compound disclosed in (15) AR-R15849, GI1817171, JMV-180, A-71378, A -71623, and SR146131, and CCK-A (cholecystokinin-A) antagonists such as the compounds disclosed in US Pat. No. 5,739,106, (16) GI-181771 (Glaxo-SmithKline), SR146131 ( Sanofisin Lab.), Butabinzide, and CN170292 (Ciliary Neurotrophic Factor) such as PD170292, PD149164 (Pfizer), (17) Axocaine (Regeneron), and WO94 / 09134, WO98 / 22128, and WO99 / 43813 As disclosed compounds CNTF derivative, (18) NN703, hexarelin, MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255, and U.S. Patent No. No. 5,536,716, 6,358,951, US patent application no. GHS (growth hormone secretagogue receptor) agonists such as those compounds disclosed in 2002/049196 and 2002/022637, and WO01 / 56592, and WO02 / 32888, (19) BVT933, DPCA37215, IK264, PNU22394, WAY161503, R-1065, and YM348, and U.S. Pat. 3,914,250, and 5HT2c (serotonin receptor, such as the compounds disclosed in WO02 / 36596, WO02 / 48124, WO02 / 10169, WO01 / 66548, WO02 / 44152, WO02 / 51844, WO02 / 40456, and WO02 / 40457. 2c) agonist, (20) Mc3r (melanocortin 3 receptor) agonist, (21) CHIR86036 (Chiron), ME-10142, and ME-10145 (Melacure), PT-141 and PT-14 (Palatin), U.S. Pat. 6,410,548, 6,294,534, 6,350,760, 6,458,790, 6,472,398, 6,376,509, and 6,818,658, U.S. Pat. US2002 / 0137664, US2003 / 0236262, US2004 / 009751, US2004 / 0092501, and WO99 / 64002, WO00 / 74679, WO01 / 991752, WO01 / 74844, WO01 / 70708, WO01 / 70337, WO01 / 91852, WO02 / 059095, WO02 / 059107, WO02 / 059108, WO02 / 059117, WO02 / 12166, WO02 / 11715, WO02 / 12178, WO02 / 15909, WO02 / 068387, WO02 / 068388, WO02 / 0678669, WO03 / 007949, and WO03 / 009847, WO04 / 024720, WO04 / 078716, WO04 / 078717, WO04 Mc4r (melanocortin 4 receptor) agonists such as the compounds disclosed in 087159, WO 04/089307 and WO 05/009950, (22) sibutratomin (Merdia (trade name) / Reductil (trade name)) and salts thereof, and US Patent No. . 4,746,680, 4,806,570, and 5,436,272, and U.S. Pat. 2002/0006964, and monoamine reuptake inhibitors such as the compounds disclosed in WO01 / 27068 and WO01 / 62341, (23) dexfenfluramine, fluoxetine, paroxetine, sertraline and US Pat. Serotonin reuptake inhibitors such as compounds disclosed in US Pat. No. 6,365,633 and WO01 / 27060 and WO01 / 162341, (24) GLP-1 (glucagon-like peptide 1) agonist, (25) Topiramate (Topimax ( (Trade name)), (26) Phyto-Farm Compound 57 (CP644, 673), (27) ACC2 (acetyl-CoA carboxylase-2) inhibitor, (28) AD9677 / TAK677 (Dainippon / Takeda), CL-316, 243, SB418790, BRL-37344, L-79568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW427353, Trecadrine, Geneca D7114, and SR59119A, and U.S. patent application no. 5,705,515, US Pat. No. 5,451,677, and WO94 / 18161, WO95 / 29159, WO97 / 46556, WO98 / 04526, WO98 / 32753, WO01 / 74782, WO02 / 32897.
(29) DGAT1 (diacylglycerol acyltransferase 1) inhibitor, (30) DGAT2 (diacylglycerol acyltransferase 2) inhibitor, (31) cerulenin and C75 FAS (fatty acid synthase) inhibitors such as: (32) PDE (phosphodiesterase) inhibitors such as theophylline, pentoxifylline, zaprinast, silidenafil, amrinone, milrinone, cilostamide, rolipram, and silomilast, (33) KB-2611 (KaroBioBMS) ), And thyroid hormone beta agonists such as the compounds disclosed in WO 02/15845 and Japanese Patent Application No. JP20000256190, (34) phytanic acid, 4-[(E) -2- (5,6) 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] benzoic acid (TTNPB), and retinoic acid, and UCP-1 such as the compounds disclosed in WO 99/00123 (Uncoupling protein 1), 2 or 3 active substances, (35) del Mar-Grasa, M .; et al. , Obesity Research, 9: 202-9 (2001), acyl-estrogens such as oleoyl-estrone, (36) glucocorticoid antagonists, (37) BVT3498, BVT2733, and WO01 / 90091, WO01 / 90090, WO 01/90092, US Pat. 6,730,690 and US patent application no. 11βHSD-1 (11-β hydroxysteroid dehydrogenase type 1) inhibitor, (38) SCD-1 (stearoyl-CoA desaturase-1) inhibitor, such as the compound disclosed in 2004/0133011, (39) isoleucine Thiazolidide, valine pyrrolizide, NVP-DPP728, LAF237, P93 / 01, TSL225, TMC-2A / 2B / 2C, FE999901, P9310 / K364, VIP01177, SDZ274-444, and U.S. Patent 6,699,871, WO03 / 004498, WO03 / 004496, EP1258476, WO02 / 083128, WO02 / 062764, WO03 / 000250, WO03 / 002530, WO03 / 002531, WO03 / 002553, WO03 Dipeptidyl peptidase IV (DP-IV) inhibitors such as the compounds disclosed in 002593, WO03 / 000180, and WO03 / 000181, (40) tetrahydrolipstatin (Orlistat / Xenical (trade name)), Triton WR1339, RHC80267, Lipstatin, Theasaponin, and Diethylumbelliferyl Phosphate, FL-386, WAY-121898, Bay-N-3176, Varilactone, Estelacin, Evelactone A, Ebelactone B, and RHC80267, and WO01 / 77094, and US Patent No. . 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644, 4,189,438, and 4,242,453 (41) fatty acid transport inhibitors, (42) dicarboxylate transport inhibitors, (43) glucose transport inhibitors, (44) phosphate transport inhibitors, (45) melanotan II Or a melanocortin agonist such as those compounds described in WO99 / 64002 and WO00 / 746799, (46) a melanin-concentrating hormone antagonist such as a compound disclosed in WO01 / 21577 and WO01 / 21169, (47) a galanin antagonist (48) CCK agonist, (49) corticotropin-releasing hormone agonist, and (50) phosphodi Sterase-3B (PDE3B) inhibitor, (51) 5HT-2 agonist, (52) histamine receptor 3 (H3) modulator, (53) β-hydroxysteroid dehydrogenase-1 (β-HSD-1) Inhibitors, (54) anti-obesity serotonin-like substances such as fenfluramine, dexfenfluramine, phentermine, and sibutramine, (55) BIM-43073D, BIM-43004C (Olitvak, DA et al., Dig. Dis. Sci. 44 (3): 643-48 (1999)), and U.S. Pat. 5,026,685, 5,604,203, 5,574,010, 5,696,093, 5,936,092, 6,046,162, 6,046,167, 6,093,692,6, 225,445, 5,604,203, 4,002,531, 4,179,337, 5,122,614, 5,349,052, 5,552,520, 6,127,355, published international patent applications Peptide YY, PYY3-36, peptide YY analogs, derivatives and fragments, such as the compounds disclosed in WO95 / 06058, WO98 / 32466, WO03 / 026591, WO03 / 057235, WO03 / 027637 and WO2004 / 066966, (56) NPY3 -36, N-acetyl- [Leu (28,31)]-NPY24-36, TAS -V, and cyclo - (28/32) -Ac- [Lys28-Glu32] - (25-36) -pNPY such as NPY2 (neuropeptide Y2) agonists, (57) Batterham et al. , J .; Clin. Endocrinol. Metab. 88: 3989-3992 (2003), NPY4 (neuropeptide Y4) agonists such as the pancreatic peptide (PP) and other Y4 agonists such as 1229U91, (58) etoroxib, celecoxib, valdecoxib, Cyclooxygenase-2 inhibitors such as parecoxib, luminacoxib, BMS347070, tiracoxib, JTE522, ABT963, CS502 and GW406381 and their pharmaceutically acceptable salts, (59) aminolex, (60) amphochloral, (61) amphetamine , (62) benzphetamine, (63) chlorphentermine, (64) clobenzolex, (65) croforex, (66) chrominolex, (67) chlortermine, (68) sai Rexedrine, (69) dexamphetamine, (70) difemethoxyzine, (71) N-ethylamphetamine, (72) fenbutrazate, (73) phenisolex, (74) fenproporex, (75 ) Fludrex, (76) fluminorex, (77) furfurylmethylamphetamine, (78) levanphetamine, (79) levofacetoperan, (80) mefenolex, (81) methanefepramon, ( 82) methamphetamine, (83) norpsoid ephedrine, (84) pentrex, (85) phendimetrazine, (86) phenmetrazine, (87) picirolex, (88) zonizamide, (89) U.S. Pat. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833 and 5, International Patent Application Publication No. 637,699; WO90 / 05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92 / 22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/2155, 93/2181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/0449 94/0496, 94/05625, 94/07743, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94 / 15903, 94/19320, 94/19332, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 9504042, 95/06645, 95/07886, 95/07908 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/2252 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96 / 16939, 96/18643, 96/20117, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554 , 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942, 97/21702, and 97/49710 Drugs (NK-1 antagonists), and (90) anti-obesity drugs such as Qnexa.

  The drug can also be combined with non-drug therapies such as exercise therapy, diet therapy, and radiation therapy.

  The compounds and combination compositions according to the present invention are effective in the treatment and prevention of diabetes. The term “diabetes” as used herein is insulin-dependent diabetes (ie, also known as IDDM, type 1 diabetes) and non-insulin-dependent diabetes (ie, also known as NIDDM, type 2 diabetes). Includes both.

  Diabetes is characterized by a fasting plasma glucose level of 126 mg / dl or higher. A diabetic patient has a fasting plasma glucose level of 126 mg / dl or greater. Prediabetes is characterized by abnormal fasting plasma glucose (FPG) values of 110 mg / dl or more and 126 mg / dl or less, impaired glucose tolerance, or insulin resistance. Pre-diabetic patients have an abnormal fasting plasma glucose value [fasting plasma glucose (FPG) value of 110 mg / dl or more and 126 mg / dl or less] or abnormal glucose tolerance (2-hour plasma glucose value of 140 mg / dl or more and 200 mg / dl or less). ) Or insulin resistance, and the risk of developing diabetes is increasing.

  The compounds or compositions according to the invention are useful for the treatment of both type 1 and type 2 diabetes. The present compounds or compositions are particularly useful for the treatment of type 2 diabetes. The compounds or compositions according to the present invention are useful for the treatment and / or prevention of prediabetes. The compounds or compositions according to the invention are also particularly useful for the treatment and / or prevention of gestational diabetes.

  Diabetes treatment refers to administration of a compound or composition according to the present invention to a diabetic patient. One outcome of treatment is to reduce the elevated glucose concentration. Another outcome of treatment is to reduce elevated insulin levels. Another outcome of treatment is to reduce elevated blood triglyceride levels.

  Another outcome of treatment is to increase insulin sensitivity. Another outcome of treatment is to improve impaired glucose tolerance. Another outcome of treatment is that insulin resistance can be reduced. Another outcome of treatment is to lower plasma insulin levels. Another outcome of treatment is to improve glycemic control, especially in type 2 diabetes. Yet another outcome of treatment is to increase the insulin sensitivity of the pancreas.

  Diabetes prevention refers to administration of a compound or a combination composition according to the present invention to a subject in need thereof for the prevention or treatment of diabetes onset, particularly in diabetes associated with obesity. The subject in need of diabetes prevention is a pre-diabetic patient.

  As used herein, the term “hypertension” is not known for its cause, or it is known for essential hypertension and its cause that result from one or more causes, such as changes in both the heart and blood vessels. Including secondary hypertension. Causes of secondary hypertension include, but are not limited to obesity, and include causes caused by certain diseases such as kidney disease, hormonal ataxia and oral contraceptives, corticosteroids, and cyclosporine. The term “hypertension” includes hypertension in which both systolic blood pressure and diastolic blood pressure are increased, and the case where diastolic blood pressure is less than 90 mmHg and systolic blood pressure is 140 mmHg or more. One outcome of treatment is to reduce elevated blood pressure.

  Dyslipidemia or lipid metabolism disorders are one or more lipids (eg cholesterol and triglycerides) and / or apolipoproteins (eg apolipoproteins A, B, C and E) and / or lipoproteins (eg lipids in the blood) Included are various conditions characterized by abnormal concentrations of lipids and apolipoproteins circulated in the body, eg, polymer complexes such as LDL, VLDL and IDL. Dyslipidemia includes atherodyslipidemia. Hyperlipidemia is accompanied by abnormal elevation of lipids, LDL and VLDL cholesterol and / or triglycerides. One outcome of treatment of dyslipidemia, including hyperlipidemia, is to reduce the increased LDL cholesterol concentration. Another outcome of treatment is to increase the lowered HDL cholesterol concentration. Another outcome of treatment is to reduce very low density lipoproteins and / or low density LDL.

  The term “metabolic syndrome”, also known as Syndrome X, is defined in Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High TP S. Ford et al., JAMA, vol.287 (3), Jan. 16, 2002, pp 356-359). For example, a person is defined as having metabolic syndrome if he has three or more symptoms of visceral obesity, hypertriglyceridemia, low HDL cholesterol, hypertension and fasting hyperglycemia. These criteria are defined in ATP-III.

The term “obesity” as used herein refers to a condition in which there is an excess of body fat, and includes built-in obesity. The definition of obesity is based on body mass index (BMI) (kg / m ² ) calculated by dividing body weight by the square of height. In Europe and the United States, obesity refers to the health status of a healthy person having a BMI of 30 kg / m ² or more or a person having at least one complication of BMI of 27 kg / m ² or more. Healthy person BMI of less than 25 kg / ^{m 2} or more 30kg / ^{m 2} and subject at risk of obesity, or a BMI of a person having at least one complication of less than 25 kg / ^{m 2} or more 27 kg / ^{m 2} Say that.

In Asians, the risk associated with obesity arises from a lower BMI than in Westerners. In Asian countries, including Japan, obesity is at least one obesity-induced or obese-related comorbidity that requires or may be ameliorated by weight loss and is 25 kg / m ² or more This refers to the health status of persons with BMI. In Asian countries, those who are at risk of becoming obese are those who have a BMI of 23 kg / m ² or more and less than 25 kg / m ² .

  As used herein, the term “obesity” encompasses all obesity as defined above.

  Comorbidities induced by or associated with obesity include, but are not limited to, diabetes, impaired glucose tolerance, insulin resistance syndrome, dyslipidemia, hypertension, hyperuricemia, ventilation, coronary artery disease, Myocardial infarction, angina pectoris, sleep apnea syndrome, pickwick syndrome, fatty liver, cerebral infarction, cerebral thrombosis, transient ischemic attack, orthopedic disease, osteoarthritis, low back pain, menstrual abnormalities and infertility Infections are included. In particular, comorbidities include hypertension, hyperlipidemia, lipid abnormalities, impaired glucose tolerance, cardiovascular diseases, sleep apnea syndrome, diabetes and other obesity related conditions.

  Treatment of obesity and obesity related diseases means administering a compound or mixture composition according to the present invention to reduce or maintain the weight of obese patients. One outcome of treatment is that the weight of an obese patient can begin to decrease relative to the weight of the patient prior to administration of the compound or mixed composition of the invention. The outcome of other treatments is that body fat, including visceral fat, can begin to decrease. The outcome of other treatments is to prevent weight gain. The outcome of other treatments is the ability to maintain a reduced weight as a result of diet, exercise or drug therapy. The outcome of other treatments is that it can reduce the onset and / or severity of obesity-related diseases. The outcome of treatment is a reduction in food intake and / or caloric intake. That is, a reduction in the total amount of food intake or a reduction in the intake of special food components such as carbohydrates or fats and / or inhibition of nutrient absorption and / or reduction in metabolic rate. The outcome of treatment is a change in metabolic rate. That is, metabolic rate changes such as preventing metabolic rate reduction or increasing metabolic rate and / or minimizing metabolic resistance, usually resulting from weight loss.

  Prevention of obesity and obesity-related diseases means administering a compound or mixed composition according to the invention to reduce or maintain the weight of a person at risk of developing obesity. One outcome of prevention is that the weight of a person at risk of developing obesity can begin to decrease compared to the weight of the patient prior to administration of the compound or mixed composition of the invention. Another preventive outcome is the ability to maintain a reduced weight as a result of diet, exercise or drug therapy. Another outcome of prevention is that the onset of obesity can be prevented if treatment is initiated before a person at risk of becoming obese presents with obesity. Another preventive outcome is that the onset and / or severity of obesity-related diseases can be reduced if treatment is initiated before a person at risk of becoming obese exhibits obesity. Furthermore, if obesity is treated, the onset and progression of obesity-related diseases can be prevented or the severity can be reduced. Such obesity-related diseases include arteriosclerosis, type 2 diabetes, polycystic ovary syndrome, cardiovascular disease, osteoarthritis, skin disease, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia And cholelithiasis, but are not limited thereto.

  The compound according to the present invention has an excellent LCE inhibitory action, and various diseases involving LCE such as cardiovascular disease, nervous system disease, metabolic disease, reproductive system disease, gastrointestinal disease, neoplasm, infection It is useful as a treatment for diseases.

  The present invention will be described more specifically with reference to production examples and reference examples, but the present invention is not limited thereto.

The thin layer chromatography of the production example used Silica gel ₆₀ F ₂₅₄ (Merck) as a plate and a UV detector as a detection method. As column silica gel, Wakogel ^™ C-300 or C-200 (Wako Pure Chemical Industries), FLASH + cartridge (Biotage) or Chromatorex (FUJI SILYSIA CHEMICAL) was used. MS spectra were measured using ZQ2000 (Waters). When NMR spectra are measured with a deuterated dimethyl sulfoxide solution, dimethyl sulfoxide is used as an internal standard, and JNM-AL400 (JEOL), Mercury 400 (400 MHz; Varian), or Inova 400 (400 MHz; Varian) type spectrometer. The total δ value was expressed in ppm.

  The meanings of the abbreviations in NMR measurement are shown below.

s: singlet d: doublet dd: double doublet t: triplet dt: double triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz DMSO-d ₆ : heavy dimethylsulfoxide Production Example 1
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl- Preparation of 3-trifluoromethyl-1H-indole-2,4-dione (1) 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1-phenyl-α- (trifluoromethyl)- Production of 1H-pyrazole-4-acetic acid methyl ester (Method 1)
To a chloroform solution (30 ml) of 3-methyl-1-phenyl-5-pyrazolone (5.0 g, 28.7 mmol) was added methyl trifluoropyruvate (3.22 mL, 28.7 mmol) at room temperature, and 2 Stir for hours. The solvent was removed under reduced pressure to obtain the title compound as a colorless solid (9.48 g).
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 2.30 (3H, s), 4.00 (3H, s), 4.06 (1H, s), 7.29 (1H, d, J = 7. 3 Hz), 7.43 (2H, t, J = 8.3 Hz), 7.60-7.70 (2H, m)
(Method 2)
Trifluoropyruvate (858 mg, 5.5 mmol) was added to ethyl acetoacetate (651 mg, 5.0 mmol), and the mixture was stirred at room temperature for 14 hours. Excess trifluoropyruvate was removed under vacuum to give 3-acetyl-2-hydroxy-2-trifluoromethyl-butanedioic acid-4-ethyl-1-methyl ester as a colorless liquid (1.43 g).

Phenylhydrazine (110 mg, 1) was added to a toluene solution (20 ml) of the obtained 3-acetyl-2-hydroxy-2-trifluoromethyl-butanedioic acid-4-ethyl-1-methyl ester (290 mg, 1.01 mmol). .01 mmol) was added and stirred for 2 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain the title compound as a colorless solid (325 mg).
(2) Preparation of 2- (1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-propanoic acid methyl ester 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1-phenyl-α- (trifluoromethyl) -1H-pyrazole-4-acetic acid methyl ester (1.5 g, 4.5 mmol) To a toluene solution (50 ml) was added thionyl chloride (2 ml, 22.5 mmol), and the mixture was stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (4.41 g).
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 2.41 (3H, s), 4.02 (3H, s), 7.23 (1H, t, J = 7.3 Hz), 7.41 (2H, t, J = 8.8 Hz), 7.80 (2H, d, J = 7.8 Hz)
(3) 3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1 —Preparation of phenyl-3-trifluoromethyl-1H-indole-2,4-dione 2- (1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)- To a chloroform solution (5 ml) of 3,3,3-trifluoro-propanoic acid methyl ester (565 mg, 1.81 mmol) was added 5,5-dimethyl-3-phenylamino-2-cyclohexen-1-one (390 mg, 1.81 mmol) was added and stirred for 14 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel flash column chromatography to obtain the title compound as a colorless solid (780 mg).
¹ HNMR (400 MHz, CDCl ₃ , δ ppm): 1.08 (3H, s), 1.12 (3H, s), 2.10-2.45 (7H, m), 7.28-7.38 ( 5H, m), 7.45-7.55 (5H, m)
ESI-MS (m / e): 496 [M + H] ⁺
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6 obtained in Preparation Example 1 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione using DAICEL CHIRALPAK AD-H (4.6 × 150 mm, 5 um, 25 ° C.), Hexane: EtOH (0.1% TFA) ) = 95: 5, optical resolution was performed under conditions of a flow rate of 0.5 ml / min and UV of 250 nm. Components having retention times of 11.5 min and 17.6 min were collected, and the optically active substance having a retention time of 11.5 min was identified as an active substance.

  The 5,5-dimethyl-3-phenylamino-2-cyclohexen-1-one used in Production Example 1 is converted into a 3-substituted-2-cyclohexen-1-one derivative, which is a raw material corresponding to the desired compound, 2- (1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-propanoic acid methyl ester each desired compound The compounds of Production Examples 2-34 were obtained in the same manner as in Production Example 1 except that the pyrazolone derivative, which is a raw material corresponding to the above, was used.

  Production Example 2
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenylmethyl Preparation of -3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained in the same manner as in Production Example 1 using 5,5-dimethyl-3-phenylmethylamino-2-cyclohexen-1-one as a starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.99 (3H, s), 1.04 (3H, s), 1.80-2.57 (7H, m), 4.54 (2H, br), 6.95-7. 45 (6H, m), 7.59-7.76 (4H, m)
ESI-MS (m / e): 510 [M + H]⁺
  Production Example 3
1- (4-Fluorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 Of 1,6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3- (4-fluorophenylamino) -2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CD₃OD, δ ppm): 1.03 (3H, s), 1.11 (3H, s), 2.20-2.40 (m, 4H), 2.45 (3H, m), 7.25-7 .40 (4H, m), 7.40-7.50 (4H, m), 7.55 (1H, m)
ESI-MS (m / e): 514 [M + H]⁺
  Production Example 4
1- (4-Chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 Preparation of 6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3- (4-chlorophenylamino) -5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CD₃OD, δ ppm): 1.03 (3H, s), 1.11 (3H, s), 2.20-2.55 (7H, m), 7.25-7.40 (5H, m), 7 .40-7.60 (4H, m)
ESI-MS (m / e): 530 [M + H]⁺
  Production Example 5
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (4-methoxyphenyl) -6 Of 1,6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained in the same manner as in Production Example 1 using 3- (4-methoxyphenylamino) -5,5-dimethyl-2-cyclohexen-1-one as the starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.04 (3H, s), 1.11 (3H, s), 2.20-2.40 (7H, m), 3.86 (3H, s), 6.97-7. 06 (2H, m), 7.15-7.30 (3H, m), 7.30-7.40 (3H, m), 7.65 (1H, m)
ESI-MS (m / e): 526 [M + H]⁺
  Production Example 6
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (3-methoxyphenyl) -6 Of 1,6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3- (3-methoxyphenylamino) -5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.10 (3H, s), 1.11 (3H, s), 2.25-2.40 (4H, m), 2.32 (3H, s), 7.15-7. 20 (4H, m), 7.23-7.29 (5H, m)
ESI-MS (m / e): 526 [M + H]⁺
  Production Example 7
1- (3-Chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 Preparation of 6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3- (3-chlorophenylamino) -5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CD₃OD, δ ppm): 1.06 (3H, s), 1.13 (3H, s), 2.25-2.40 (4H, m), 2.46 (3H, s), 7.29 (2H , T, J = 7.3 Hz), 7.38 (1H, d, J = 6.8 Hz), 7.46 (2H, t, J = 8.3 Hz), 7.30-7.70 (4H, m)
ESI-MS (m / e): 530 [M + H]⁺
  Production Example 8
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1,6,6-trimethyl-3- Production of trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3-methylamino-2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.13 (3H, s), 1.16 (3H, s), 2.21-2.52 (4H, m), 2.55 (3H, s), 3.21 (3H, s), 7.09-7.17 (1H, m), 7.26-7.34 (2H, m), 7.69 (2H, d, J = 7.8 Hz)
ESI-MS (m / e): 434 [M + H]⁺
  Production Example 9
1-ethyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3-ethylamino-5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.10-1.40 (9H, m), 2.05 (3H, s), 2.10-2.65 (4H, m), 4.12 (2H, q, J = 7) .3 Hz), 7.45-7.50 (3H, m), 7.70-7.80 (2H, m)
ESI-MS (m / e): 448 [M + H]⁺
  Production Example 10
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-propyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3-propylamino-2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δppm): 0.95-1.04 (3H, m), 1.09-1.22 (6H, m), 2.03-2.63 (11H, m), 7.33-7.45. (3H, m), 7.67-7.77 (2H, m)
ESI-MS (m / e): 462 [M + H]⁺
  Production Example 11
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1-isopropyl-6,6-dimethyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3-isopropylamino-2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.10-1.30 (9H, m), 1.52 (3H, s), 1.59 (3H, s), 2.10-2.70 (4H, m), 4. 32 (1H, m), 7.34-7.45 (3H, m), 7.66-7.81 (2H, m)
ESI-MS (m / e): 462 [M + H]⁺
  Production Example 12
1-cyclopropyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3-cyclopropylamino-5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.11-1.23 (9H, m), 1.90-2.48 (5H, m), 2.60 (3H, s), 4.27 (1H, br), 7. 31-7.47 (3H, m), 7.67-7.76 (2H, m)
ESI-MS (m / e): 460 [M + H]⁺
  Production Example 13
1-cyclobutyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3-cyclobutylamino-5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.10-1.30 (12H, m), 1.80-2.60 (3H, m), 3.44-3.52 (4H, m), 4.32 (1H, m) ), 7.34-7.42 (3H, m), 7.61-7.81 (2H, m)
ESI-MS (m / e): 474 [M + H]⁺
  Production Example 14
1-cyclopentyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using cyclopentylamino-5,5-dimethyl-3--2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.9-1.12 (13H, m), 2.00-2.50 (6H, m), 2.64-2.75 (3H, m), 7.31-7.47 (3H, m), 7.67-7.76 (2H, m)
ESI-MS (m / e): 488 [M + H]⁺
  Production Example 15
1-cyclohexyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 3-cyclohexylamino-5,5-dimethyl-2-cyclohexen-1-one as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.08-1.23 (12H, m), 1.70-2.60 (12H, m), 7.34-7.45 (3H, m), 7.65-7.78. (2H, m)
ESI-MS (m / e): 502 [M + H]⁺
  Production Example 16
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (2 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3- (2-pyridylmethylamino) -2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.08 (6H, s), 2.26 (3H, s), 2.19-2.81 (4H, m), 4.81 (1H, d, J = 14.6 Hz), 5.00 (1H, d, J = 15.6 Hz), 7.07 (1 H, m), 7, 22-7.29 (2 H, m), 7.33 (1 H, d, J = 7.8 Hz) ), 7.70 (4H, m), 8.50 (1H, d, J = 4.4 Hz)
ESI-MS (m / e): 511 [M + H]⁺
  Production Example 17
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (3 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3- (3-pyridylmethylamino) -2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.03 (3H, s), 1.06 (3H, s), 2.15-2.56 (7H, m), 4.57 (1H, d, J = 17.0 Hz), 5.17 (1H, d, J = 16.6 Hz), 7.05-7.22 (1H, m), 7.29-7.38 (2H, m), 7.06-7.76 (4H , M), 8.52-8.61 (2H, m)
ESI-MS (m / e): 511 [M + H]⁺
  Production Example 18
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (4 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5,5-dimethyl-3- (4-pyridylmethylamino) -2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.07 (3H, s), 2.20-2.55 (7H, m), 4.66 (1H, m), 5.16 (1H, m), 7.15-7.23 (3H, m), 7.34-7.43 (2H, m), 7.60-7.70 (1H, m), 7.72 (1H, d, J = 8.8 Hz), 8.64 (2H, d, J = 4.9 Hz)
ESI-MS (m / e): 511 [M + H]⁺
  Production Example 19
3- (3-Ethyl-2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl- Production of 3-trifluoromethyl-1H-indole-2,4-dione
  The raw material was 2- (3-ethyl-1,5-dihydro-5-oxo-1-phenyl-4H-pyrazole-4-ylidene) -3,3,3-trifluoro-propanoic as in Production Example 1. The title compound was obtained using acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.79 (3H, s), 1.05 (3H, s), 1.39 (3H, t, J = 7.3 Hz), 2.09-2.19 (2H, m), 2.26-2.51 (4H, m), 7.32-7.46 (4H, m), 7.47-7.62 (4H, m), 7.81 (2H, d, J = 7) .8Hz)
ESI-MS (m / e): 510 [M + H]⁺
  Production Example 20
3- (3-Cyclopropyl-2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl Preparation of -3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the raw material was 2- (3-cyclopropyl-1,5-dihydro-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-propano. The title compound was obtained using ic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.94-1.27 (8H, m), 1.04 (3H, s), 2.27-2.55 (4H, m), 7.14 (1H, t, J = 7) .3 Hz), 7.27-7.62 (8 H, m), 7.75 (1 H, d, J = 7.8 Hz)
ESI-MS (m / e): 522 [M + H]⁺
  Production Example 21
3- (2,5-Dihydro-5-oxo-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- Preparation of phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- (1,5-dihydro-3-trifluoromethyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-prop The title compound was obtained using Neuc acid methyl ester.
¹HNMR (400 MHz, CD₃OD, δ ppm): 1.08 (3H, s), 1.10 (3H, s), 2.12-2.26 (2H, m), 2.38-2.47 (2H, m), 7 .34-7.59 (5H, m), 7.73-7.80 (1H, m), 7.84-7.90 (4H, m)
ESI-MS (m / e): 550 [M + H]⁺
  Production Example 22
3- [1- (3-Chlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl- Preparation of 1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1- (3-chlorophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro. -The title compound was obtained using propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.04 (3H, s), 1.11 (3H, s), 2.00-2.48 (4H, m), 2.50 (3H, s), 7.13 (1H, d, J = 7.8 Hz), 7.12-7.29 (2H, m), 7.31 (1H, d, J = 5.4 Hz), 7.41 (1H, d, J = 7.3 Hz) ), 7.47-7.59 (3H, m), 7.74 (1H, d, J = 9.3 Hz)
ESI-MS (m / e): 530 [M + H]⁺
  Production Example 23
3- [1- (4-Chlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl- Preparation of 1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1- (4-chlorophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro. -The title compound was obtained using propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.12 (3H, s), 2.07-2.17 (2H, m), 2.30-2.47 (2H, m), 2. 49 (3H, s), 7.28-7.34 (3H, m), 7.32 (1H, m), 7.50-7.58 (4H, m), 7.77 (1H, d, J = 9.2Hz)
ESI-MS (m / e): 530 [M + H]⁺
  Production Example 24
3- [2,5-Dihydro-1- (2-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-1- (2-methoxyphenyl) -3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.13 (3H, s), 2.16-2.46 (2H, m), 2.47 (3H, s), 3.90 (3H, s), 6.93-7.05 (2H, m), 7.12-7.26 (1H, m), 7.43-7.53 (4H, m), 7.12-7.26 ( 1H, m), 7.80 (1H, dd, J = 7.8, 1.5 Hz)
ESI-MS (m / e): 526 [M + H]⁺
  Production Example 25
3- [2,5-dihydro-1- (3-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-1- (3-methoxyphenyl) -3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.12 (3H, s), 2.13 (1H, d, J = 9.8 Hz), 2.16 (1H, d, J = 12.2 Hz) ), 2.29-2.44 (2H, m), 2.50 (3H, s), 3.81 (3H, s), 7.37-7.45 (4H, m), 7.49- 7.58 (5H, m)
ESI-MS (m / e): 526 [M + H]⁺
  Production Example 26
3- [2,5-Dihydro-1- (4-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-1- (4-methoxyphenyl) -5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.10 (3H, s), 2.08-2.17 (2H, m), 2.23-2.45 (2H, m), 2. 47 (3H, s), 3.79 (3H, s), 6.82 (1H, d, J = 9.3 Hz), 6.87 (1H, d, J = 7.3 Hz), 7.31- 7.66 (7H, m)
ESI-MS (m / e): 526 [M + H] +
  Production Example 27
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6-methyl-1-phenyl-3- Production of trifluoromethyl-1H-indole-2,4-dione
  The title compound was obtained using 5-methyl-3-phenylamino-2-cyclohexen-1-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.99-1.05 (3H, m), 1.98-2.51 (8H, m), 7.00-7.10 (1H, m), 7.17-7.31. (4H, m), 7.46-7.56 (3H, m), 7.63 (2H, t, J = 7.8 Hz)
ESI-MS (m / e): 482 [M + H]⁺
  Production Example 28
3 ′-(2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -1′-phenyl-3′-trifluoromethyl-3 ′, 7′-dihydro Preparation of spiro [cyclobutane-1,6′-indole] -2 ′, 4 ′ (1′H, 5′H) -dione
  The title compound was obtained using 8-anilino-spiro [3.5] non-7-en-6-one as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.86-1.95 (2H, m), 2.18-2.24 (3H, m), 2.39-2.64 (4H, m), 3.35-3.49. (2H, m), 3.70-3.83 (2H, m), 7.11-7.18 (1H, m), 7.27-7.37 (4H, m), 7.47-7 .63 (5H, m)
ESI-MS (m / e): 508 [M + H]⁺
  Production Example 29
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -4H-pyrazol-4-ylidene] -3,3,3. The title compound was obtained using -trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.12 (3H, s), 2.07-2.49 (4H, m), 2.52 (3H, s), 7.29-7. 50 (2H, m), 7.47-7.67 (6H, m), 7.98 (1H, d, J = 8.8 Hz)
ESI-MS (m / e): 564 [M + H]⁺
  Production Example 30
3- [1- (4-Fluorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1- (4-fluoromethylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3- The title compound was obtained using trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.12 (3H, s), 2.07-2.47 (4H, m), 2.49 (3H, s), 6.99-7. 10 (2H, m), 7.29-7.35 (1H, m), 7.41 (1H, d, J = 6.8 Hz), 7.48-7.58 (4H, m), 7. 73-7.78 (1H, m,)
ESI-MS (m / e): 514 [M + H]⁺
  Production Example 31
3- [1- (4-Cyanophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1- (4-cyanophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.04 (3H, s), 1.09 (3H, s), 2.01-2.56 (4H, m), 2.51 (3H, s), 7.25-7. 34 (2H, m), 7.38-7.45 (1H, m), 7.47-7.66 (5H, m), 7.80-7.92 (1H, m)
ESI-MS (m / e): 521 [M + H]⁺
  Production Example 32
3- [2,5-Dihydro-1- (4-isopropylphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-1- (4-isopropylphenyl) -3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.11 (3H, s), 1.21 (3H, s), 1.23 (3H, s), 2.08-2.45 (4H, m), 2.49 (3H, s), 2.83-2.92 (1H, m), 7.16-7.25 (3H, m), 7.35-7.57 (5H, m) , 7.64 (1H, d, J = 8.3 Hz)
ESI-MS (m / e): 538 [M + H]⁺
  Production Example 33
3- [2,5-Dihydro-3-methyl-1- (4-methylphenyl) -5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-1- (4-methylphenyl) -5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.04 (3H, s), 1.11 (3H, s), 2.07-2.42 (7H, m), 2.48 (3H, s), 7.14 (2H, d, J = 8.3 Hz), 7.31-7.57 (6H, m), 7.62 (1H, d, J = 8.8 Hz)
ESI-MS (m / e): 510 [M + H]⁺
  Production Example 34
3- [1- (4-Aminosulfonylphenyl) -2,5-dihydro-5-oxo-3-trifluoromethyl-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6 Preparation of 6-dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-5-oxo-1- (4-sulfoamidophenyl) -4H-pyrazol-4-ylidene] -3,3,3- The title compound was obtained using trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.10 (6H, s), 1.98-2.76 (7H, m), 7.14 (1H, br), 7.37-7.64 (8H, m).
ESI-MS (m / e): 575 [M + H]⁺
  Production Example 35
3- [1- (4-tert-Butylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  2- [1- (4-tert-Butylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3 as a raw material by the same method as in Production Example 1 , 3-Trifluoro-propanoic acid methyl ester was used to give the title compound.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.10 (3H, s), 1.29 (9H, s), 2.09-2.53 (7H, m), 7.11-7. 22 (2H, m), 7.23-7.69 (9H, m)
ESI-MS (m / e): 552 [M + H]⁺
  Production Example 36
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -4H-pyrazol-4-ylidene] -3,3,3. The title compound was obtained using -trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.10 (3H, s), 2.05-2.52 (7H, m), 7.11-7.22 (2H, m), 7. 29-7.43 (2H, m), 7.47-7.62 (4H, m), 7.85 (1H, d, J = 9.2 Hz)
ESI-MS (m / e): 580 [M + H]⁺
  Production Example 37
3- [2,5-Dihydro-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-4H-pyrazol-4-ylidene] -3,3,3. The title compound was obtained using -trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.10 (3H, s), 2.12-2.52 (10H, m), 6.80 (1H, s), 7.18 (1H, s), 7.33-7.61 (6H, m)
ESI-MS (m / e): 524 [M + H]⁺
  Production Example 38
3- [1- (4-cyclohexylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1- (4-cyclohexylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.11 (3H, s), 1.30-1.45 (5H, m), 1.68-1.91 (6H, m), 2. 08-2.52 (7H, m), 7.15-7.27 (3H, m), 7.36-7.66 (6H, m)
ESI-MS (m / e): 578 [M + H]⁺
  Production Example 39
3- [1- (4-Benzylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1- (4-benzylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.12 (3H, s), 2.09-2.19 (1H, m), 2.25-2.51 (6H, m), 3. 93-4.00 (2H, m), 7.11-7.43 (10H, m), 7.45-7.60 (4H, m)
ESI-MS (m / e): 586 [M + H]⁺
  Production Example 40
3- [2,5-dihydro-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3- The title compound was obtained using trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.17 (3H, br), 1.31 (6H, d, J = 5.9 Hz), 2.09-2.50 (7H, m), 4.43-4.61 (1H , M), 6.79-6.95 (2H, m), 7.32-7.65 (5H, m)
ESI-MS (m / e): 554 [M + H]⁺
  Production Example 41
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-phenoxyphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl Preparation of -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-5-oxo-1- (4-phenoxyphenyl) -4H-pyrazol-4-ylidene] -3,3,3-tri The title compound was obtained using fluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.07 (3H, s), 1.12 (3H, s), 2.09-2.53 (7H, m), 6.94-7.13 (7H, m), 7. 28-7.43 (4H, m), 7.46-7.59 (3H, m)
ESI-MS (m / e): 588 [M + H]⁺
  Production Example 42
3- [2,5-Dihydro-3-methyl-5-oxo-1- (biphenyl-4-yl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-5-oxo-1- (biphenyl-4-yl) -4H-pyrazol-4-ylidene] -3,3,3- The title compound was obtained using trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.05 (3H, s), 1.11 (3H, s), 2.10-2.53 (7H, m), 7.31-7.38 (2H, m), 7. 40-7.47 (4H, m), 7.53-7.62 (8H, m)
ESI-MS (m / e): 572 [M + H]⁺
  Production Example 43
3- [1- (3,5-Dichlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2-[(3,5-dichlorophenyl) -1,5-dihydro-3-methyl-5-oxo-1-4H-pyrazol-4-ylidene] -3,3,3- The title compound was obtained using trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.07 (3H, s), 1.11 (3H, s), 2.09-2.45 (7H, m), 7.12-7.17 (1H, m), 7. 28-7.34 (1H, m), 7.38-7.44 (1H, m), 7.49-7.60 (4H, m), 7.83 (1H, d, J = 2.0 Hz) )
ESI-MS (m / e): 565 [M + H]⁺
  Production Example 44
3- [2,5-dihydro-3-methyl- (4-methylsulfonylphenyl) -5-oxo-l lH-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Preparation of dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione
  In the same manner as in Production Example 1, the starting material was 2- [1,5-dihydro-3-methyl-1- (4-methylsulfonylphenyl) -5-oxo-4H-pyrazol-4-ylidene] -3,3,3- The title compound was obtained using trifluoro-propanoic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (3H, s), 1.12 (3H, s), 2.18-2.54 (7H, m), 3.04 (3H, s), 7.28-7. 38 (5H, m), 7.28-7.35 (1H, m), 7.41 (1H, d, J = 8.0 Hz), 7.49-7.60 (3H, m), 7. 85 (2H, br), 7.92 (1H, d, J = 8.8 Hz), 8.09 (1H, d, J = 8.8 Hz)
ESI-MS (m / e): 574 [M + H]⁺
  Reference example 1
Production of 3- (1-cyclobutylamino) -5,5-dimethyl-2-cyclohexen-1-one
  To a toluene solution (30 ml) of 1,3-cyclohexanedione (1.40 g, 10.0 mmol), cyclopentylamine (782 mg, 11.0 mmol) and boron trifluoride diethyl ether complex (1.56 g, 11.0 mmol) were added at room temperature. The mixture was added and stirred for 14 hours under reflux. The reaction solution was concentrated under reduced pressure, and 5% aqueous sodium hydroxide solution was added. The reaction solution was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to give the title compound as a yellow oil. (1.64g)
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.06 (6H, s), 1.77-1.96 (4H, m), 2.17 (4H, d, J = 7.3 Hz), 2.36-2.46 (2H) , M), 3.85-3.95 (1H, m)
  Reference example 2
Preparation of 3- (1-cyclopentylamino) -5,5-dimethyl-2-cyclohexen-1-one
  In the same manner as in Reference Example 1, the title compound was obtained using cyclopentylamine as a starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.77-0.90 (4H, m), 1.11 (3H, s), 1.14 (3H, s), 1.21-1.35 (2H, m), 1. 50-1.64 (2H, m), 2.20 (2H, m), 2.49 (2H, br)
  Reference example 3
Preparation of 3-ethyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  To a chloroform solution (5 ml) of 3-ethyl-1-phenyl-5-pyrazolone (94 mg, 0.5 mmol) was added methyl trifluoropyruvate (78 mg, 0.5 mmol) at room temperature, and the mixture was stirred at 80 ° C. for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a colorless solid (172 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.25 (3H, t, J = 7.6 Hz), 2.71 (2H, q, J = 7.8 Hz) 15.4, 3.98 (3H, s), 4.05 ( 1H, s), 7.14-7.30 (2H, m), 7.36-7.45 (2H, m), 7.63 (1H, br), 7.84 (1H, d, J = 8.8Hz)
ESI-MS (m / e): 345 [M + H]⁺
  Reference example 4
Preparation of 2- (3-ethyl-1,5-dihydro-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-propanoic acid methyl ester
  A toluene solution of 3-ethyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (172 mg, 0.5 mmol) ( 5 ml) was added with thionyl chloride (0.365 ml, 5.0 mmol) and stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (163 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.36 (3H, t, J = 7.3 Hz), 2.75 (2H, dd, J = 14.4, 7.1 Hz), 4.01 (3H, s), 7.16 -7.22 (1H, m), 7.41 (2H, t, J = 8.8 Hz), 7.84 (2H, d, J = 7.8 Hz)
ESI-MS (m / e): 327 [M + H]⁺
  Reference Example 5
Preparation of 3-cyclopropyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 3-cyclopropyl-1-phenyl-5-pyrazolone (100 mg, 0.5 mmol) at room temperature and stirred at 80 ° C. for 2 hours. . The solvent was removed under reduced pressure to give the title compound as a colorless solid (178 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.73-1.27 (4H, m), 1.27-1.81 (1H, m), 3.98 (3H, s), 4.06 (1H, s), 7. 14-7.22 (1H, m), 7.33-7.45 (3H, m), 7.63 (1H, br), 7.79 (1H, d, J = 8.8 Hz)
ESI-MS (m / e): 357 [M + H]⁺
  Reference Example 6
Preparation of 2- (3-cyclopropyl-1,5-dihydro-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-propanoic acid methyl ester
  Toluene solution of 3-cyclopropyl-α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (178 mg, 0.5 mmol) (5 ml) was added with thionyl chloride (0.365 ml, 5.0 mmol) and stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (169 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 0.99-1.04 (2H, m), 1.10-1.15 (2H, m),), 1.93-2.01 (1H, m) 4.02 (3H, s), 7.16-7.24 (2H, m), 7.36-7.42 (2H, m), 7.79 (2H, d, J = 8.8 Hz)
ESI-MS (m / e): 339 [M + H]⁺
  Reference Example 7
Preparation of α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-3-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  To a chloroform solution (5 ml) of 1-phenyl-3-trifluoromethyl-5-pyrazolone (114 mg, 0.5 mmol) was added methyl trifluoropyruvate (78 mg, 0.5 mmol) at room temperature, and the mixture was stirred at 80 ° C. for 2 hours. did. The solvent was removed under reduced pressure to obtain the title compound as a colorless solid (172 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 4.07 (3H, s), 4.31 (1H, s), 7.38 (1H, t, J = 7.3 Hz), 7.48 (2H, t, J = 7.3 Hz) ), 7.71 (2H, d, J = 8.8 Hz)
ESI-MS (m / e): 385 [M + H]⁺
  Reference Example 8
Preparation of 2- (1,5-dihydro-3-trifluoromethyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene) -3,3,3-trifluoro-propanoic acid methyl ester
  Toluene of α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-3-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (192 mg, 0.5 mmol) To the solution (5 ml) was added thionyl chloride (0.365 ml, 5.0 mmol), and the mixture was stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (183 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 4.04 (3H, s), 7.43-7.52 (2H, m), 7.66-7.71 (1H, m), 7.74-7.78 (2H, m) )
ESI-MS (m / e): 367 [M + H]⁺
  Reference Example 9
Preparation of 1- (3-chlorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of (3-chlorophenyl) -3-methyl-1-5-pyrazolone (104 mg, 0.5 mmol) at room temperature, and 2 at 80 ° C. Stir for hours. The solvent was removed under reduced pressure to obtain the title compound as a colorless solid (182 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.33 (3H, s), 3.98 (3H, s), 4.01 (1H, s), 7.14-7.30 (2H, m), 7.58-7. 66 (1H, m), 7.72-7.80 (1H, m)
ESI-MS (m / e): 365 [M + H]⁺
  Reference Example 10
Of 2- [1- (3-Chlorophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing
  1- (3-Chlorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (182 mg, 0.5 mmol) To a toluene solution (5 ml) was added thionyl chloride (0.365 ml, 5.0 mmol), and the mixture was stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (173 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, s), 4.02 (3H, s), 7.17-7.22 (1H, m), 7.33 (1H, t, J = 8.3 Hz), 7.75-7.79 (1 H, m), 7.90 (1 H, t, J = 2.0 Hz)
ESI-MS (m / e): 347 [M + H]⁺
  Reference Example 11
Preparation of 1- (4-chlorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  To a chloroform solution (5 ml) of 1- (4-chlorophenyl) -3-methyl-5-pyrazolone (104 mg, 0.5 mmol) was added methyl trifluoropyruvate (78 mg, 0.5 mmol) at room temperature, and 2 at 80 ° C. Stir for hours. The solvent was removed under reduced pressure to obtain the title compound as a colorless solid (182 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.32 (3H, s), 3.98 (3H, s), 4.01 (1H, s), 7.35-7.41 (2H, m), 7.59-7. 65 (2H, m)
ESI-MS (m / e): 365 [M + H]⁺
  Reference Example 12
2- [1- (4-Chlorophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing
  1- (4-Chlorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (182 mg, 0.5 mmol) To a toluene solution (5 ml) was added thionyl chloride (0.365 ml, 5.0 mmol), and the mixture was stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (173 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, s), 4.02 (3H, s), 7.36 (2H, d, J = 9.3 Hz), 7.79 (2H, d, J = 8.8 Hz) )
ESI-MS (m / e): 347 [M + H]⁺
  Reference Example 13
Preparation of 2,5-dihydro-α-hydroxy-1- (2-methoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  To a toluene solution (5 ml) of 3-acetyl-2-hydroxy-2-trifluoromethyl-butanedioic acid-4-ethyl-1-methyl ester (143 mg, 0.5 mmol) at room temperature was added 2-methoxyphenylhydrazine (78 mg). , 0.5 mmol), and stirred at 80 ° C. for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a pale yellow solid (180 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.36 (3H, s), 3.84 (3H, s), 3.88 (3H, s), 3.99 (1H, s), 7.14-7.21 (2H, m), 7.22-7.29 (2H, m)
ESI-MS (m / e): 361 [M + H]⁺
  Reference Example 14
2- [1,5-Dihydro-1- (2-methoxyphenyl) -3-methyl-5-oxo-4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  2,5-Dihydro-α-hydroxy-1- (2-methoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.36 (3H, s), 3.92 (3H, s), 3.93 (3H, s), 7.20-7.15 (2H, m), 7.23-7. 28 (2H, m)
ESI-MS (m / e): 343 [M + H]⁺
  Reference Example 15
Preparation of 2,5-dihydro-α-hydroxy-1- (3-methoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  To a chloroform solution (5 ml) of 1- (3-methoxyphenyl) -3-methyl-5-pyrazolone (102 mg, 0.5 mmol) was added methyl trifluoropyruvate (78 mg, 0.5 mmol) at room temperature, and at 80 ° C. Stir for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a pale yellow solid (180 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, s), 3.98 (3H, s), 4.00 (1H, s), 4.02 (3H, s), 7.14-7.20 (1H, m), 7.23-7.34 (2H, m), 7.41-7.43 (1H, m)
ESI-MS (m / e): 361 [M + H]⁺
  Reference Example 16
2- [1,5-Dihydro-1- (3-methoxyphenyl) -3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  2,5-Dihydro-α-hydroxy-1- (3-methoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, s), 3.83 (3H, s), 4.02 (3H, s), 7.15-7.20 (1H, m), 7.23-7. 33 (2H, m), 7.41-7.44 (1H, m)
ESI-MS (m / e): 343 [M + H]⁺
  Reference Example 17
Preparation of 2,5-dihydro-α-hydroxy-1- (4-methoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 1- (4-methoxyphenyl) -3-methyl-5-pyrazolone (102 mg, 0.5 mmol) at room temperature, and then at 80 ° C. Stir for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a pale yellow solid (180 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.26 (3H, s), 3.82 (3H, s), 3.97 (1H, s), 3.98 (3H, s), 6.88-6.95 (1H, m), 7.45 (2H, br)
ESI-MS (m / e): 361 [M + H]⁺
  Reference Example 18
2- [1,5-Dihydro- (4-methoxyphenyl) -3-methyl-1-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  2,5-Dihydro-α-hydroxy-1- (4-methoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.39 (3H, s), 3.82 (3H, s), 4.00 (3H, s), 6.92 (2H, d, J = 9.3 Hz), 7.68 ( 2H, d, J = 9.3Hz)
ESI-MS (m / e): 343 [M + H]⁺
  Reference Example 19
Preparation of 8-anilino-spiro [3.5] none-7-en-6-one
  The title compound was obtained in the same manner as in Reference Example 1 using spiro [3.5] nonane-6,8-dione as a starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.85-1.97 (6H, m), 2.48 (2H, s), 2.57 (2H, s), 5.57 (1H, s), 6.11 (1H, br), 7.14-7.19 (3H, m), 7.31-7.37 (2H, m)
  Reference Example 20
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-acetic acid methyl ester
  4-Acetyl-2-hydroxy-2-trifluoromethyl-butanedioic acid-4-ethyl-1-methyl ester (143 mg, 0.5 mmol) in chloroform solution (5 ml) at room temperature with 4-trifluorophenylhydrazine ( 88 mg, 0.5 mmol) was added and the mixture was stirred at 80 ° C. for 2 hours. The solvent was removed under reduced pressure to give the title compound as a pale yellow solid (199 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.36 (3H, s), 4.04 (3H, br), 3.97 (3H, s), 4.07 (1H, s), 7.15-7.20 (1H, m), 7.64-7.70 (2H, m)
ESI-MS (m / e): 399 [M + H]⁺
  Reference Example 21
2- [1,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid Production of methyl ester
  2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1- (4-trifluoromethylphenyl) -1H-pyrazole-4-acetic acid methyl ester (180 mg, 0 0.5 mmol) in toluene solution (5 ml) was added thionyl chloride (0.365 ml, 5.0 mmol) and stirred under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.44 (3H, s), 3.82 (3H, s), 4.02 (1H, s), 4.03 (3H, s), 7.66 (2H, d, J = 8.8 Hz), 8.01 (2H, d, J = 8.3 Hz)
ESI-MS (m / e): 381 [M + H]⁺
  Reference Example 22
Preparation of 1- (4-fluorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 1- (4-fluorophenyl) -3-methyl-5-pyrazolone (96 mg, 0.5 mmol) at room temperature, and then at 80 ° C. Stir for 2 hours. The solvent was removed under reduced pressure to give the title compound as a pale yellow solid (174 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.29 (3H, s), 4.00 (3H, br), 4.05 (1H, s), 7.06-7.15 (2H, m), 7.56-7. 68 (2H, m)
ESI-MS (m / e): 349 [M + H]⁺
  Reference Example 23
2- [1- (4-Fluorophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  1- (4-Fluorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, m), 4.01 (1H, s), 4.03 (3H, s), 7.07-7.13 (2H, m), 7.76-7. 82 (2H, m)
ESI-MS (m / e): 331 [M + H]⁺
  Reference Example 24
Preparation of 1- (4-cyanophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyltrifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 1- (4-cyanophenyl) -3-methyl-5-pyrazolone (100 mg, 0.5 mmol) at room temperature, and then at 80 ° C. Stir for 2 hours. The solvent was removed under reduced pressure to give the title compound as a pale yellow solid (174 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.33 (3H, s), 3.98 (3H, s), 4.02 (1H, s), 7.70 (2H, d, J = 8.3 Hz), 7.92− 7.9 (2H, m)
ESI-MS (m / e): 356 [M + H]⁺
  Reference Example 25
2- [1- (4-Cyanophenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  1- (4-Cyanophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.44 (3H, m), 4.03 (3H, s), 7.70 (2H, d, J = 9.3 Hz), 7.76-7.82 (2H, d, J = 8.8Hz)
ESI-MS (m / e): 338 [M + H]⁺
  Reference Example 26
Preparation of 2,5-dihydro-α-hydroxy-1- (4-isopropylphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 1- (4-isopropylphenyl) -3-methyl-5-pyrazolone (108 mg, 0.5 mmol) at room temperature, and then at 80 ° C. Stir for 2 hours. The solvent was removed under reduced pressure to give the title compound as a pale yellow solid (186 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.25 (6H, dd, J = 2.0, 6.8 Hz), 2.36 (3H, s), 2.86-2.97 (1H, m), 3.98 (3H , S), 4.00 (1H, s), 7.14-7.20 (2H, m), 7.22-7.30 (2H, m)
ESI-MS (m / e): 373 [M + H]⁺
  Reference Example 27
2- [1,5-Dihydro-1- (4-isopropylphenyl) -3-methyl-5-oxo-4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  2,5-Dihydro-α-hydroxy-1- (4-isopropylphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (171 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.24 (6H, d, J = 6.8 Hz), 2.40 (3H, m), 2.86-2.96 (1H, m), 2.40 (3H, m), 3.99 (1H, s), 4.00 (3H, s), 7.23-7.26 (2H, m), 7.68 (2H, d, J = 8.8 Hz)
ESI-MS (m / e): 355 [M + H]⁺
  Reference Example 28
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-1- (4-methylphenyl) -5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 3-methyl-1- (4-methylphenyl) -5-pyrazolone (94 mg, 0.5 mmol) at room temperature, and at 80 ° C. Stir for 2 hours. The solvent was removed under reduced pressure to give the title compound as a pale yellow solid (172 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.27 (3H, s), 2.36 (3H, s), 3.97 (3H, s), 4.05 (1H, s), 7.20 (2H, d, J = 8.8 Hz), 7.67 (2H, d, J = 8.8 Hz)
ESI-MS (m / e): 345 [M + H]⁺
  Reference Example 29
2- [1,5-Dihydro-3-methyl-1- (4-methylphenyl) -5-oxo-4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  2,5-dihydro-α-hydroxy-3-methyl-1- (4-methylphenyl) -5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (172 mg, 0.5 mmol ) Was added to a toluene solution (5 ml), and thionyl chloride (0.365 ml, 5.0 mmol) was added thereto, followed by stirring under reflux for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (163 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.35 (3H, s), 2.40 (3H, m), 4.00 (3H, s), 7.20 (2H, d, J = 8.3 Hz), 7.70 ( 2H, d, J = 8.8Hz)
ESI-MS (m / e): 327 [M + H]⁺
  Reference Example 30
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (4-sulfoamidophenyl) -α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  Methyl trifluoropyruvate (78 mg, 0.5 mmol) was added to a chloroform solution (5 ml) of 3-methyl-1- (4-sulfoamidophenyl) -5-pyrazolone (205 mg, 0.5 mmol) at room temperature, and 80 ° C. For 2 hours. The solvent was removed under reduced pressure to give the title compound as a pale yellow solid (196 mg).
¹HNMR (400 MHz, DMSO-d₆, Δ ppm): 2.31 (3H, s), 3.81 (3H, s), 7.85-7.94 (4H, m)
ESI-MS (m / e): 410 [M + H]⁺
  Reference Example 31
2- [1,5-Dihydro-3-methyl-5-oxo-1- (4-sulfoamidophenyl) -4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl Esters production
  2,5-Dihydro-α-hydroxy-3-methyl-5-oxo-1- (4-sulfoamidophenyl) -α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (172 mg,. To a toluene solution (5 ml) of 5 mmol) was added thionyl chloride (0.365 ml, 5.0 mmol), and the mixture was stirred for 3 hours under reflux. The reaction solution was concentrated under reduced pressure to obtain the title compound as a reddish brown solid (163 mg).
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.45 (3H, m), 4.03 (3H, s), 7.15-7.20 (4H, m)
ESI-MS (m / e): 392 [M + H]⁺
  Reference Example 32
Preparation of 1- (4-tert-butylphenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained in the same manner as in Production Example 1 using 4-tert-butylphenylhydrazine as a starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.33 (9H, s), 2.30 (3H, s), 3.99 (3H, br), 4.05 (1H, s),
7.43 (2H, d, J = 8.8 Hz), 7.53 (2H, d, J = 7.3 Hz)
ESI-MS (m / e): 387 [M + H]⁺
  Reference Example 33
2- [1- (4-tert-Butylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid Production of methyl ester
  1- (4-tert-Butylphenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4 as a raw material by the same method as in Production Example 1 The title compound was obtained using acetic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.32 (9H, s), 2.42 (3H, s), 4.01 (3H, s), 7.41 (2H, d, J = 8.8 Hz), 7.68 ( 2H, d, J = 8.8Hz)
ESI-MS (m / e): 369 [M + H]
  Reference Example 34
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained in the same manner as in Production Example 1 using 4-trifluoromethoxyphenylhydrazine as a starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.31 (3H, s), 4.03 (3H, br), 4.06 (1H, s), 7.15-7.29 (2H, m), 7.74 (2H, d, J = 8.3 Hz)
ESI-MS (m / e): 415 [M + H]⁺
  Reference Example 35
2- [1,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid Production of methyl ester
  In the same manner as in Production Example 1, the starting material was 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -α-trifluoromethyl-1H-pyrazole-4-acetate. The title compound was obtained using tic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.42 (3H, s), 4.02 (3H, s), 7.26 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 9.3 Hz) )
ESI-MS (m / e): 397 [M + H]
  Reference Example 36
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained using 3,5-dimethylphenylhydrazine as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.29 (3H, s), 2.34 (6H, s), 4.02 (3H, s), 4.05 (1H, s), 6.92 (1H, s), 7 .14-7.20 (1H, m), 7.46 (1H, d, J = 7.8 Hz)
ESI-MS (m / e): 359 [M + H]⁺
  Reference Example 37
2- [1,5-Dihydro-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid Production of methyl ester
  In the same manner as in Production Example 1, 2,5-dihydro-α-hydroxy-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetate was used. The title compound was obtained using tic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.34 (6H, s), 2.36 (3H, s), 4.02 (3H, s), 7.18 (2H, s), 7.43 (1H, s)
ESI-MS (m / e): 341 [M + H]
  Reference Example 38
Preparation of 1- (4-cyclohexylphenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained in the same manner as in Production Example 1 using 4-cyclohexylphenylhydrazine as a starting material.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.32-1.46 (5H, m), 1.77-1.92 (5H, m), 2.28 (3H, s), 2.36 (1H, s), 2. 47-2.55 (1H, m), 3.97 (3H, s), 4.04 (1H, s), 6.91 (2H, d, J = 9.3 Hz), 7.14-7. 20 (1H, m), 7.46 (1H, d, J = 7.8 Hz)
ESI-MS (m / e): 413 [M + H]⁺
  Reference Example 39
2- [1- (4-cyclohexylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  In the same manner as in Production Example 1, the starting material was 1- (4-cyclohexylphenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid. The title compound was obtained using methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.32-1.46 (5H, m), 1.77-1.92 (5H, m), 2.39 (3H, s), 2.47-2.55 (1H, m ), 4.00 (3H, 1), 7.15-7.28 (3H, m), 7.67 (1H, d, J = 8.3 Hz)
ESI-MS (m / e): 395 [M + H]
  Reference Example 40
Preparation of 1- (4-benzylphenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained using 4-benzylphenylhydrazine as the starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.29 (3H, s), 3.99 (2H, s), 4.00 (3H, s), 4.51-4.58 (1H, m), 6.91 (2H, d, J = 9.3 Hz), 7.14-7.20 (1H, m), 7.46 (1H, d, J = 7.8 Hz)
ESI-MS (m / e): 421 [M + H]⁺
  Reference Example 41
2- [1- (4-Benzylphenyl) -1,5-dihydro-3-methyl-5-oxo-4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  In the same manner as in Production Example 1, the starting material was 1- (4-benzylphenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid. The title compound was obtained using methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.39 (3H, s), 3.98 (2H, s), 4.00 (3H, m), 6.91 (2H, d, J = 8.8 Hz), 7.13- 7.33 (8H, m), 7.70 (2H, d, J = 8.8 Hz)
ESI-MS (m / e): 403 [M + H]
  Reference Example 42
2,5-dihydro-α-hydroxy-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl esterManufacturing of
  The title compound was obtained using 4-isopropoxyphenylhydrazine as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 1.33 (6H, d, J = 6.4 Hz) 2.39 (3H, s), 3.98 (3H, s), 4.00 (3H, s), 4.51-4 .58 (1H, m), 6.91 (2H, d, J = 9.3 Hz), 7.14-7.20 (1H, m), 7.46 (1H, d, J = 7.8 Hz)
ESI-MS (m / e): 371 [M + H]⁺
  Reference Example 43
2- [1,5-Dihydro-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl esterManufacturing of
  In the same manner as in Production Example 1, the raw material was 2,5-dihydro-α-hydroxy-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic The title compound was obtained using acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, s), 4.01 (3H, s), 4.50-4.58 (1H, m), 6.91 (2H, d, J = 8.8 Hz), 7.15-7.20 (1H, m), 7.65 (2H, d, J = 8.8 Hz)
ESI-MS (m / e): 405 [M + H]
  Reference Example 44
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (4-phenoxyphenyl) -α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained using 4-phenoxyphenylhydrazine as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.30 (3H, s), 4.03 (3H, s), 4.05 (1H, s), 6.99-7.10 (4H, m), 7.30-7. 37 (3H, m), 7.72-7.77 (2H, m)
ESI-MS (m / e): 423 [M + H]⁺
  Reference Example 45
2- [1,5-Dihydro-3-methyl-5-oxo-1- (4-phenoxyphenyl) -4H-pyrazole-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl ester Manufacturing of
  In the same manner as in Production Example 1, the raw material was 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (4-phenoxyphenyl) -α-trifluoromethyl-1H-pyrazole-4-acetic acid. The title compound was obtained using methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.41 (3H, s), 4.01 (3H, s), 6.97-7.09 (3H, m), 7.30-7.38 (4H, m), 7. 73-7.77 (2H, m)
ESI-MS (m / e): 405 [M + H]
  Reference Example 46
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (biphenyl-4-yl) -α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained using biphenyl-4-ylhydrazine as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.33 (3H, s), 4.01 (3H, s), 4.06 (1H, s), 7.33-7.39 (2H, m), 7.42-7. 48 (4H, m), 7.56-7.67 (8H, m)
ESI-MS (m / e): 389 [M + H]⁺
  Reference Example 47
2- [1,5-Dihydro-3-methyl-5-oxo-1- (biphenyl-4-yl) -4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl Esters production
  In the same manner as in Production Example 1, the raw material was 2,5-dihydro-α-hydroxy-3-methyl-5-oxo-1- (biphenyl-4-yl) -α-trifluoromethyl-1H-pyrazole-4-acetic The title compound was obtained using acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.43 (3H, s), 4.03 (3H, s), 7.32-7.39 (2H, m), 7.41-7.68 (4H, m), 7. 57-7.68 (8H, m)
ESI-MS (m / e): 389 [M + H]
  Reference Example 48
Preparation of 1- (3,5-dichlorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained using 3,5-dichlorophenylhydrazine as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.31 (3H, s), 4.04 (3H, s), 4.06 (1H, s), 7.24 (1H, s), 7.86 (2H, d, J = 4.0Hz)
ESI-MS (m / e): 400 [M + H]⁺
  Reference Example 49
2-[(3,5-dichlorophenyl) -1,5-dihydro-3-methyl-5-oxo-1-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl Esters production
  In the same manner as in Production Example 1, the starting material was 1- (3,5-dichlorophenyl) -2,5-dihydro-α-hydroxy-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic. The title compound was obtained using acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.42 (3H, s), 4.03 (3H, s), 7.23 (1H, m), 8.12 (2H, d, J = 9.3 Hz)
ESI-MS (m / e): 382 [M + H]
  Reference Example 50
Preparation of 2,5-dihydro-α-hydroxy-3-methyl-1- (4-methylsulfonylphenyl) -5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester
  The title compound was obtained using 4-methylsulfonylphenylhydrazine as a starting material in the same manner as in Production Example 1.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.33 (3H, s), 3.06 (3H, s), 3.98 (3H, s), 4.08 (1H, s), 7.17 (2H, d, J = 8.3 Hz), 7.98 (2H, d, J = 9.0 Hz)
ESI-MS (m / e): 409 [M + H]⁺
  Reference Example 51
2- [1,5-Dihydro-3-methyl-1- (4-methylsulfonylphenyl) -5-oxo-4H-pyrazol-4-ylidene] -3,3,3-trifluoro-propanoic acid methyl Esters production
  In the same manner as in Production Example 1, the raw material was 2,5-dihydro-α-hydroxy-3-methyl-1- (4-methylsulfonylphenyl) -5-oxo-α- (trifluoromethyl) -1H-pyrazole-4- The title compound was obtained using acetic acid methyl ester.
¹HNMR (400 MHz, CDCl₃, Δ ppm): 2.45 (3H, s), 3.07 (3H, s), 4.04 (3H, s), 7.98 (2H, d, J = 9.3 Hz), 8.12 ( 2H, d, J = 9.3Hz)
ESI-MS (m / e): 310 [M + H]

  The compound according to the present invention has an excellent LCE inhibitory action and is useful as a therapeutic agent for various diseases associated with LCE, such as cardiovascular diseases, nervous system diseases, metabolic diseases, reproductive diseases, gastrointestinal diseases. It is.

Claims (20)

Formula (Ia)

[Where:
R ^1a and R ^2a are each independently substituted with a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group, and a heteroaryl group. Means an optionally substituted lower alkyl group;
R ^4a and R ^5a each independently represents a lower alkyl group, a cyclo lower alkyl group, an aryl group or an aralkyl group, or R ^4a and R ^5a together represent a cyclo lower alkylidene together with an adjacent carbon atom. May form a group;
R ^6a means a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group or a lower alkoxy lower alkyl group; the cyclo lower alkyl group, cyclo lower alkylidene group, aryl group, aralkyl group and heteroaryl group are each independently And may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ^3a represents a lower alkyl group which may be substituted with a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group. The cyclo lower alkyl group, aryl group and heteroaryl group in R ^3a are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group , Lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , _{^{-N (R 7) COR 8,}} -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R _{^{, -SR 7, -SO 2 R 7}} , -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl And X represents —N (R ⁷ ) — or —O— (wherein R ^2a is a hydrogen atom, R ^3a is a phenyl group, and R ^4a , R ^5a and R ^6a are methyl groups). R ^1a is n-butyl group, phenyl group, 4-fluorophenyl group, 3-chlorophenyl group, 3,4-dichlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 3-trifluoromethyl. Phenyl group, 4-methoxyphenyl group, furfuryl group, benzyl group, phenethyl group, 4-fluorobenzyl group, 2-chlorobenzyl group or 3,4-dimethoxyphenethyl group. Or a salt thereof not taste). R ^3a is a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl ^{group, -CON (R 7) R 8} , -N (R 7) R 8, -N (R 7) COR 8, -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) _{^{R 8, -SR 7, -SO 2}} R 7, -SO 2 N (R 7) R 8 and,

The compound or a salt thereof according to claim 1, which is a phenyl group substituted with one or two substituents selected from the group consisting of: R ^1a is phenyl, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, propyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4-chlorophenyl group or 3-methoxyphenyl group The compound according to claim 1 or a salt thereof . The compound or a salt thereof according to claim 3 , wherein R ^1a is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. 1- (4-Chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (3-methoxyphenyl) -6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1,6,6-trimethyl-3- Trifluoromethyl-1H-indole-2,4-dione,
1-ethyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-propyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1-isopropyl-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclopropyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl -3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclobutyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclopentyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
1-cyclohexyl-3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (2 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (3 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- (4 -Pyridylmethyl) -3-trifluoromethyl-1H-indole-2,4-dione,
3- (3-Ethyl-2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (3-Cyclopropyl-2,5-dihydro-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl -3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-5-oxo-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1- Phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (3-Chlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl- 1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Chlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl- 1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-1- (2-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-dihydro-1- (3-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-1- (4-methoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -1-phenyl-3,5,6,7-tetrahydro-6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6-methyl-1-phenyl-3- Trifluoromethyl-1H-indole-2,4-dione,
3 ′-(2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -1′-phenyl-3′-trifluoromethyl-3 ′, 7′-dihydro Spiro [cyclobutane-1,6′-indole] -2 ′, 4 ′ (1′H, 5′H) -dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethylphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Fluorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Cyanophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-1- (4-isopropylphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-1- (4-methylphenyl) -5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Aminosulfonylphenyl) -2,5-dihydro-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl-1- Phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-tert-Butylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-trifluoromethoxyphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-1- (3,5-dimethylphenyl) -5-oxo-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6 -Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-cyclohexylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (4-Benzylphenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-dihydro-1- (4-isopropoxyphenyl) -3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (4-phenoxyphenyl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6-dimethyl -1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [2,5-Dihydro-3-methyl-5-oxo-1- (biphenyl-4-yl) -1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- [1- (3,5-Dichlorophenyl) -2,5-dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl] -3,5,6,7-tetrahydro-6,6- Dimethyl-1-phenyl-3-trifluoromethyl-1H-indole-2,4-dione, or 3- [2,5-dihydro-3-methyl- (4-methylsulfonylphenyl) -5-oxo-1- 1H- pyrazol-4-yl] -3,5,6,7- tetrahydro-6,6-dimethyl-1-phenyl-3 according to claim 1, wherein trifluoromethyl -1H- indole-2,4-dione Or a salt thereof . Formula (I)

[Where:
R ¹ and R ² are each independently substituted with a substituent selected from the group consisting of a hydrogen atom, a cyclo-lower alkyl group, an aryl group, a heteroaryl group, or a cyclo-lower alkyl group, an aryl group, and a heteroaryl group. Means an optionally substituted lower alkyl group;
R ⁴ and R ⁵ each independently represents a lower alkyl group, a cyclo lower alkyl group, an aryl group or an aralkyl group, or R ⁴ and R ⁵ together with an adjacent carbon atom together with a cyclo lower alkylidene May form a group;
R ⁶ represents a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group or a lower alkoxy lower alkyl group; the cyclo lower alkyl group, cyclo lower alkylidene group, aryl group, aralkyl group and heteroaryl group are each independently And may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ³ represents a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a lower alkyl group which may be substituted with a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group. The cyclo lower alkyl group, aryl group and heteroaryl group in R ³ are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group , Lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , _{^{-N (R 7) COR 8,}} -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R 8, _{^{SR 7, -SO 2 R 7,}} -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, aryl group or heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ are each independently a hydrogen atom or lower alkyl It refers to the group; and X is -N (R 7) ^- or -O- compound represented by the meaning] or long chain fatty acid elongation enzyme (LCE) inhibitor a salt thereof as an active ingredient. The long-chain fatty acid elongation enzyme (LCE) according to claim 6 , wherein R ² of the compound of the general formula (I) or a salt thereof is a hydrogen atom, R ³ is a phenyl group, and R ⁴ , R ⁵ and R ⁶ are methyl groups. Inhibitor. The long chain fatty acid elongation enzyme (LCE ) according to claim 7 , wherein R ¹ of the compound of the general formula (I) or a salt thereof is a phenyl group, a benzyl group, a 3-chlorophenyl group, a 4-fluorophenyl group or a 4-methoxyphenyl group. ) Inhibitors. R ³ of the compound of general formula (I) or a salt thereof is a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, a heteroaryl group, an aryloxy group, an aralkyl ^{group, -CON (R 7) R 8} , -N (R 7) R 8, -N (R 7) COR 8, -N (R 7) SO 2 R 8 ^{, -OCOR 7, -OCON (R 7} ) R 8, -SR 7, -SO 2 R 7, -SO 2 N (R 7) R 8 and,

The long-chain fatty acid elongation enzyme (LCE) inhibitor according to claim 6, which is a phenyl group substituted with one or two substituents selected from the group consisting of: R ¹ of the compound of the general formula (I) or a salt thereof is cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, propyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4- The long-chain fatty acid elongation enzyme (LCE) inhibitor according to claim 6, which is a chlorophenyl group or a 3-methoxyphenyl group. The long-chain fatty acid elongation enzyme (LCE) inhibitor according to claim 10 , wherein R ¹ of the compound of the general formula (I) or a salt thereof is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. 3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenylmethyl -3-trifluoromethyl-1H-indole-2,4-dione,
1- (4-Fluorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (4-methoxyphenyl) -6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione, or 1- (3-chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl -1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione or a salt thereof The long-chain fatty acid elongation enzyme (LCE) inhibitor according to claim 6, which is an active ingredient. A therapeutically effective amount of the general formula (I)

[Where:
R ¹ and R ² are each independently substituted with a substituent selected from the group consisting of a hydrogen atom, a cyclo-lower alkyl group, an aryl group, a heteroaryl group, or a cyclo-lower alkyl group, an aryl group, and a heteroaryl group. Means an optionally substituted lower alkyl group;
R ⁴ and R ⁵ each independently represents a lower alkyl group, a cyclo lower alkyl group, an aryl group or an aralkyl group, or R ⁴ and R ⁵ together with an adjacent carbon atom together with a cyclo lower alkylidene May form a group;
R ⁶ represents a lower alkyl group, a halo lower alkyl group, a cyclo lower alkyl group or a lower alkoxy lower alkyl group; the cyclo lower alkyl group, cyclo lower alkylidene group, aryl group, aralkyl group and heteroaryl group are each independently And may be substituted with a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halo lower alkyl group and a lower alkoxy group;
R ³ represents a hydrogen atom, a cyclo lower alkyl group, an aryl group, a heteroaryl group, or a lower alkyl group which may be substituted with a substituent selected from the group consisting of a cyclo lower alkyl group, an aryl group and a heteroaryl group. The cyclo lower alkyl group, aryl group and heteroaryl group in R ³ are each independently unsubstituted or a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group , Lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, heteroaryl group, aryloxy group, aralkyl group, -CON (R ⁷ ) R ⁸ , -N (R ⁷ ) R ⁸ , _{^{-N (R 7) COR 8,}} -N (R 7) SO 2 R 8, -OCOR 7, -OCON (R 7) R 8, _{^{SR 7, -SO 2 R 7,}} -SO 2 N (R 7) R 8 and,

Means a cyclo-lower alkyl group, an aryl group or a heteroaryl group substituted with 1 or 2 substituents selected from the group consisting of: R ⁷ and R ⁸ each independently represents a hydrogen atom or a lower alkyl A group; and X represents —N (R ⁷ ) — or —O—] or a salt thereof ,
And a pharmaceutical composition for the treatment of diabetes, obesity or non-alcoholic fatty liver, comprising pharmaceutically acceptable additives. The pharmaceutical composition according to claim 13 , wherein R ² of the compound of the general formula (I) or a salt thereof is a hydrogen atom, R ³ is a phenyl group, and R ⁴ , R ⁵ and R ⁶ are methyl groups. The pharmaceutical composition according to claim 14 , wherein R ¹ of the compound of the general formula (I) or a salt thereof is a phenyl group, a benzyl group, a 3-chlorophenyl group, a 4-fluorophenyl group or a 4-methoxyphenyl group. R ³ of the compound of general formula (I) or a salt thereof is a halogen atom, nitro group, cyano group, lower alkyl group, halo lower alkyl group, lower alkoxy group, halo lower alkoxy group, carboxyl group, cyclo lower alkyl group, aryl group, a heteroaryl group, an aryloxy group, an aralkyl ^{group, -CON (R 7) R 8} , -N (R 7) R 8, -N (R 7) COR 8, -N (R 7) SO 2 R 8 ^{, -OCOR 7, -OCON (R 7} ) R 8, -SR 7, -SO 2 R 7, -SO 2 N (R 7) R 8 and,

The pharmaceutical composition according to claim 13, which is a phenyl group substituted with one or two substituents selected from the group consisting of: R ¹ of the compound of the general formula (I) or a salt thereof is cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, propyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 4- The pharmaceutical composition according to claim 13, which is a chlorophenyl group or a 3-methoxyphenyl group. The pharmaceutical composition according to claim 17 , wherein R ¹ of the compound of the general formula (I) or a salt thereof is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. The pharmaceutical composition according to claim 13 , which is used for treatment of diabetes . 3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenyl- 3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-1-phenylmethyl -3-trifluoromethyl-1H-indole-2,4-dione,
1- (4-Fluorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione,
3- (2,5-Dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-1- (4-methoxyphenyl) -6 , 6-Dimethyl-3-trifluoromethyl-1H-indole-2,4-dione, or 1- (3-chlorophenyl) -3- (2,5-dihydro-3-methyl-5-oxo-1-phenyl -1H-pyrazol-4-yl) -3,5,6,7-tetrahydro-6,6-dimethyl-3-trifluoromethyl-1H-indole-2,4-dione or a salt thereof and 14. The pharmaceutical composition according to claim 13, comprising a pharmaceutically acceptable additive.